Compositions and Methods for Lowering Triglycerides Without Raising LDL-C Levels in a Subject on Concomitant Statin Therapy

ABSTRACT

In various embodiments, the present invention provides compositions and methods for treating and/or preventing cardiovascular-related diseases in subject in need thereof.

PRIORITY CLAIM

This application is a continuation of U.S. patent application Ser. No.15/411,500 filed Jan. 20, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/496,429 filed Sep. 25, 2014, which claimspriority to U.S. Provisional Patent Application Ser. No. 61/889,315,filed on Oct. 10, 2013, the entire contents of each of which areincorporated herein by reference and relied upon.

BACKGROUND

Cardiovascular disease is one of the leading causes of death in theUnited States and most European countries. It is estimated that over 70million people in the United States alone suffer from a cardiovasculardisease or disorder including but not limited to high blood pressure,coronary heart disease, dyslipidemia, congestive heart failure andstroke.

SUMMARY

In various embodiments, the present invention provides pharmaceuticalcompositions and methods of using such compositions to treat and/orprevent cardiovascular-related diseases. In one embodiment, the subjectis on concomitant statin therapy. In another embodiment, the subject onstatin therapy has a baseline fasting serum triglyceride level of about200 mg/dL to about 500 mg/dL.

In one embodiment, the invention provides a method of loweringtriglycerides in a subject on statin therapy having baseline fastingtriglycerides of about 200 mg/dl to about 500 mg/dl, the methodcomprising administering to the subject about 4 g of ethyleicosapentaenoate per day.

In another embodiment, the invention provides a method of loweringtriglycerides and LDL-C in a subject comprising, administering orally toa subject having fasting triglycerides of about 200 mg/dl to less than500 mg/dl who is on stable statin therapy about 4 g per day of apharmaceutical composition comprising at least about 90%, by weight, ofall fatty acids (and/or derivatives thereof) present, ethyleicosapentaenoate for a period of at least about 12 weeks.

In one embodiment, the invention provides a method of loweringtriglycerides in a subject on stable statin therapy having baselinefasting triglycerides of about 200 mg/dl to about 500 mg/dl, the methodcomprising administering to the subject a pharmaceutical compositioncomprising polyunsaturated fatty acids, for example about 1 g to about 4g of EPA per day, wherein upon administering the composition to thesubject daily for a period of 12 weeks the subject exhibits at least 5%lower fasting triglycerides than a control subject maintained on stablestatin therapy (optionally with placebo matching the EPA) withoutconcomitant EPA for a period of 12 weeks wherein the control subjectalso has baseline fasting triglycerides of about 200 mg/dl to about 500mg/dl. In another embodiment, upon administering the composition to thesubject daily for a period of 12 weeks the subject exhibits no serumLDL-C increase, no statistically significant serum LDL-C increase, aserum LDL-C decrease, or the subject is statistically non-inferior tothe control subjects (statin plus optional placebo) in regard to serumLDL-C elevation).

These and other embodiments of the present invention will be disclosedin further detail herein below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the correlation of atherogenic lipoproteins with Apo Bafter 12 weeks of treatment with ethyl eicosapentaenoate.

FIG. 2A displays placebo-adjusted percent changes in FADI parameterscompared to baseline in plasma for both 2 g/day and 4 g/day doses ofethyl eicosapentaenoate.

FIG. 2B displays placebo-adjusted percent changes in FADI parameterscompared to baseline in red blood cells for both 2 g/day and 4 g/daydoses of ethyl eicosapentaenoate.

FIG. 3 displays median percent change in fasting triglycerides frombaseline to week 12 in a modified intent-to-treat (“MITT”) studypopulation.

FIG. 4 displays median percent change from baseline for selectedendpoints.

FIG. 5A displays percent change in fasting triglycerides plotted againstpercent change in EPA concentration in plasma from baseline to week 12for the MITT study population.

FIG. 5B displays percent change in fasting triglycerides plotted againstpercent change in EPA concentration in red blood cells from baseline toweek 12 for the MITT study population.

FIG. 6A displays a regression fit plot of atherogenic particleconcentration to Apo B concentration at baseline for subjects assignedto placebo group (◯) or to a treatment group (+).

FIG. 6B displays a regression fit plot of atherogenic particleconcentration to Apo B concentration after 12 weeks of receiving placebo(◯) or 4 g per day of a composition consistent with the presentdisclosure (+).

FIG. 6C displays a regression fit plot of total LDL particleconcentration to Apo B concentration at baseline for subjects assignedto placebo group (◯) or to a treatment group (+).

FIG. 6D displays a regression fit plot of total LDL particleconcentration to Apo B concentration after 12 weeks of receiving placebo(◯) or 4 g per day of a composition consistent with the presentdisclosure (+).

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any manner. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

The use of numerical values in the various quantitative values specifiedin this application, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about.” Also, thedisclosure of ranges is intended as a continuous range including everyvalue between the minimum and maximum values recited as well as anyranges that can be formed by such values. Also disclosed herein are anyand all ratios (and ranges of any such ratios) that can be formed bydividing a disclosed numeric value into any other disclosed numericvalue. Accordingly, the skilled person will appreciate that many suchratios, ranges, and ranges of ratios can be unambiguously derived fromthe numerical values presented herein and in all instances such ratios,ranges, and ranges of ratios represent various embodiments of thepresent invention.

In one embodiment, the invention provides a method for treatment and/orprevention of cardiovascular-related diseases. The term“cardiovascular-related disease” herein refers to any disease ordisorder of the heart or blood vessels (i.e. arteries and veins) or anysymptom thereof. Non-limiting examples of cardiovascular-related diseaseand disorders include hypertriglyceridemia, hypercholesterolemia, mixeddyslipidemia, coronary heart disease, vascular disease, stroke,atherosclerosis, arrhythmia, hypertension, myocardial infarction, andother cardiovascular events.

The term “treatment” in relation a given disease or disorder, includes,but is not limited to, inhibiting the disease or disorder, for example,arresting the development of the disease or disorder; relieving thedisease or disorder, for example, causing regression of the disease ordisorder; or relieving a condition caused by or resulting from thedisease or disorder, for example, relieving, preventing or treatingsymptoms of the disease or disorder. The term “prevention” in relationto a given disease or disorder means: preventing the onset of diseasedevelopment if none had occurred, preventing the disease or disorderfrom occurring in a subject that may be predisposed to the disorder ordisease but has not yet been diagnosed as having the disorder ordisease, and/or preventing further disease/disorder development ifalready present.

In one embodiment, the present invention provides a method of bloodlipid therapy comprising administering to a subject or subject group inneed thereof a pharmaceutical composition as described herein. Inanother embodiment, the subject or subject group hashypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/orvery high triglycerides.

In another embodiment, the subject or subject group being treated has abaseline triglyceride level (or mean or median baseline triglyceridelevel in the case of a subject group), fed or fasting, of about 200mg/dl to about 500 mg/dl. In another embodiment, the subject or subjectgroup has a baseline LDL-C level (or mean or median baseline LDL-Clevel), despite stable statin therapy, of about 40 mg/dl to about 115 orabout 40 to about 100 mg/dl.

In one embodiment, the subject or subject group being treated inaccordance with methods of the invention is on concomitant statintherapy, for example atorvastatin, rosuvastatin or simvastatin therapy(with or without ezetimibe). In another embodiment, the subject is onconcomitant stable statin therapy at time of initiation of ultra-pureEPA therapy.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention has a body mass index (BMI ormean BMI) of not more than about 45 kg/m².

In one embodiment, the invention provides a method of loweringtriglycerides in a subject on stable statin therapy having baselinefasting triglycerides of about 200 mg/dl to about 500 mg/dl, the methodcomprising administering to the subject a pharmaceutical compositioncomprising about 1 g to about 4 g of EPA (e.g. ultra-pure EPA), whereinupon administering the composition to the subject daily for a period ofabout 12 weeks the subject exhibits at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, or at least 75% lower fasting triglycerides than a control subjectmaintained on stable statin therapy (and optionally placebo matching theultra-pure EPA) without concomitant ultra-pure EPA for a period of about12 weeks, wherein the control subject also has baseline fastingtriglycerides of about 200 mg/dl to about 500 mg/dl. The term “stablestatin therapy” herein means that the subject, subject group, controlsubject or control subject group in question has been taking a stabledaily dose of a statin (e.g. atorvastatin, rosuvastatin or simvastatin)for at least 4 weeks prior to the baseline fasting triglyceridemeasurement (the “qualifying period”). For example, a subject or controlsubject on stable statin therapy would receive a constant daily (i.e.the same dose each day) statin dose for at least 4 weeks immediatelyprior to baseline fasting triglyceride measurement. In one embodiment,the subject's and control subject's LDL-C is maintained between about 40mg/dl and about 115 mg/dl or about 40 mg/dl to about 100 mg/dl duringthe qualifying period. The subject and control subject are thencontinued on their stable statin dose for the 12 week period postbaseline.

In one embodiment, the statin is administered to the subject and thecontrol subject in an amount of about 1 mg to about 500 mg, about 5 mgto about 200 mg, or about 10 mg to about 100 mg, for example about 1 mg,about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg,about 8 mg, about 9 mg, or about 10 mg; about 15 mg, about 20 mg, about25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425mg, about 450 mg, about 475 mg, or about 500 mg. In another embodiment,the subject (and optionally the control subject) has a baseline LDL-Clevel, despite stable statin therapy, of about 40 mg/dl to about 115mg/dl or about 40 mg/dl to about 100 mg/dl. In another embodiment, thesubject and/or control subject has a body mass index (BMI; or mean BMI)of not more than about 45 kg/m².

In another embodiment, the invention provides a method of loweringtriglycerides in a subject group on stable statin therapy having meanbaseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl,the method comprising administering to members of the subject group apharmaceutical composition comprising about 1 g to about 4 g ofultra-pure EPA per day, wherein upon administering the composition tothe members of the subject group daily for a period of about 12 weeksthe subject group exhibits at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75% lower mean fasting triglycerides than a control subject groupmaintained on stable statin therapy without concomitant ultra-pure EPA(optionally with matching placebo) for a period of about 12 weeks,wherein the control subject group also has mean baseline fastingtriglycerides of about 200 mg/dl to about 500 mg/dl. In a relatedembodiment, the stable statin therapy will be sufficient such that thesubject group has a mean LDL-C level about at least about 40 mg/dl andnot more than about 100 mg/dl or about 40 mg/dl to about 100 mg/dl forthe 4 weeks immediately prior to the baseline fasting triglyceridemeasurement.

In another embodiment, the invention provides a method of loweringtriglycerides in subject group on stable statin therapy and having amean baseline fasting triglyceride level of about 200 mg/dl to about 500mg/dl, the method comprising administering to members of the subjectgroup a pharmaceutical composition comprising about 1 g to about 4 g ofultra-pure EPA, wherein upon administering the composition to members ofthe subject group daily for a period of about 12 weeks the subject groupexhibits: (a) at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75% lowermean fasting triglycerides by comparison with a control subject groupmaintained on stable statin therapy without concomitant ultra-pure EPA(optionally with matching placebo) for a period of about 12 weeks, and(b) no serum LDL-C increase, no statistically significant serum LDL-Cincrease, a serum LDL-C decrease, or the subject is statisticallynon-inferior to the control subjects (statin plus optional placebo) inregard to serum LDL-C elevation) no increase in mean serum LDL-C levelscompared to baseline, wherein the control subject also has mean baselinefasting triglycerides of about 200 mg/dl to about 500 mg/dl.

In another embodiment, the invention provides a method of loweringtriglycerides in subject on stable statin therapy and having meanbaseline fasting triglyceride level of about 200 mg/dl to about 500mg/dl, the method comprising administering to the subject apharmaceutical composition comprising about 1 g to about 4 g ofultra-pure EPA, wherein upon administering the composition to thesubject daily for a period of about 12 weeks the subject exhibits (a) atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, or at least 75% lower fastingtriglycerides by comparison with a control subject maintained on stablestatin therapy without concomitant ultra-pure EPA for a period of about12 weeks and (b) no increase in serum LDL-C levels compared to baseline,wherein the control subject also has baseline fasting triglycerides ofabout 200 mg/dl to about 500 mg/dl.

In another embodiment, the invention provides a method of loweringtriglycerides in subject group on stable statin therapy and having meanbaseline fasting triglyceride level of about 200 mg/dl to about 500mg/dl, the method comprising administering to members of the subjectgroup a pharmaceutical composition comprising about 1 g to about 4 g ofultra-pure EPA, wherein upon administering the composition to themembers of the subject group daily for a period of about 12 weeks thesubject group exhibits: (a) at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75% lower mean fasting triglycerides and (b) at least 5%, at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45% or at least 50% lower mean serum LDL-Clevels by comparison with a control subject group maintained on stablestatin therapy without concomitant ultra-pure EPA (optionally withmatching placebo) for a period of about 12 weeks, no serum LDL-Cincrease, no statistically significant serum LDL-C increase, nostatistically significant serum LDL-C increase, a serum LDL-C decrease,or the subject group is statistically non-inferior to the controlsubject group (statin plus optional placebo) in regard to serum LDL-Celevation), wherein the control subject group also has mean baselinefasting triglycerides of about 200 mg/dl to about 500 mg/dl.

In another embodiment, the invention provides a method of loweringtriglycerides in subject group on stable statin therapy and having meanbaseline fasting triglyceride level of about 200 mg/dl to about 500mg/dl, the method comprising administering to members of the subjectgroup a pharmaceutical composition comprising about 1 g to about 4 g ofultra-pure EPA, wherein upon administering the composition to themembers of the subject group daily for a period of about 12 weeks thesubject group exhibits (a) at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75% lower mean fasting triglycerides and (b) at least 5%, at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45% or at least 50% lower mean serum LDL-Clevels by comparison with a control subject group maintained on stablestatin therapy without concomitant ultra-pure EPA (optionally withmatching placebo) for a period of about 12 weeks, no serum LDL-Cincrease, no statistically significant serum LDL-C increase, nostatistically significant serum LDL-C increase, a serum LDL-C decrease,or the subject group is statistically non-inferior to the controlsubject group (statin plus optional placebo) in regard to serum LDL-Celevation), wherein the control subject group also has mean baselinefasting triglycerides of about 200 mg/dl to about 500 mg/dl.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a fasting baselineabsolute plasma level of free total fatty acid (or mean thereof) notgreater than about 300 nmol/ml, not greater than about 250 nmol/ml, notgreater than about 200 nmol/ml, not greater than about 150 nmol/ml, notgreater than about 100 nmol/ml, or not greater than about 50 nmol/ml.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a fasting baselineabsolute plasma level of free EPA (or mean thereof in the case of asubject group) not greater than about 0.70 nmol/ml, not greater thanabout 0.65 nmol/ml, not greater than about 0.60 nmol/ml, not greaterthan about 0.55 nmol/ml, not greater than about 0.50 nmol/ml, notgreater than about 0.45 nmol/ml, or not greater than about 0.40 nmol/ml.In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a baseline fastingplasma level (or mean thereof) of free EPA, expressed as a percentage oftotal free fatty acid, of not more than about 3%, not more than about2.5%, not more than about 2%, not more than about 1.5%, not more thanabout 1%, not more than about 0.75%, not more than about 0.5%, not morethan about 0.25%, not more than about 0.2% or not more than about 0.15%.In one such embodiment, free plasma EPA and/or total fatty acid levelsare determined prior to initiating therapy.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a fasting baselineabsolute plasma level of free EPA (or mean thereof) not greater thanabout 1 nmol/ml, not greater than about 0.75 nmol/ml, not greater thanabout 0.50 nmol/ml, not greater than about 0.4 nmol/ml, not greater thanabout 0.35 nmol/ml, or not greater than about 0.30 nmol/ml.

In another embodiment, the subject or subject group being treated inaccordance with methods of the invention exhibits a fasting baselineplasma, serum or red blood cell membrane EPA level not greater thanabout 150 μg/ml, not greater than about 125 μg/ml, not greater thanabout 100 μg/ml, not greater than about 95 μg/ml, not greater than about75 μg/ml, not greater than about 60 μg/ml, not greater than about 50μg/ml, not greater than about 40 μg/ml, not greater than about 30 μg/ml,or not greater than about 25 μg/ml.

In another embodiment, methods of the present invention comprise a stepof measuring the subject's (or subject group's mean) baseline lipidprofile prior to initiating therapy. In another embodiment, methods ofthe invention comprise the step of identifying a subject or subjectgroup having one or more of the following: baseline non-HDL-C value (ormean) of about 200 mg/dl to about 400 mg/dl, for example at least about210 mg/dl, at least about 220 mg/dl, at least about 230 mg/dl, at leastabout 240 mg/dl, at least about 250 mg/dl, at least about 260 mg/dl, atleast about 270 mg/dl, at least about 280 mg/dl, at least about 290mg/dl, or at least about 300 mg/dl; baseline total cholesterol value (ormean) of about 250 mg/dl to about 400 mg/dl, for example at least about260 mg/dl, at least about 270 mg/dl, at least about 280 mg/dl or atleast about 290 mg/dl; baseline vLDL-C value (or mean) of about 140mg/dl to about 200 mg/dl, for example at least about 150 mg/dl, at leastabout 160 mg/dl, at least about 170 mg/dl, at least about 180 mg/dl orat least about 190 mg/dl; baseline HDL-C value (or mean) of about 10 toabout 100 mg/dl, for example not more than about 90 mg/dl not, not morethan about 80 mg/dl, not more than about 70 mg/dl, not more than about60 mg/dl, not more than about 60 mg/dl, not more than about 50 mg/dl,not more than about 40 mg/dl, not more than about 35 mg/dl, not morethan about 30 mg/dl, not more than about 25 mg/dl, not more than about20 mg/dl, or not more than about 15 mg/dl; and/or baseline LDL-C value(or mean) of about 30 to about 300 mg/dl, for example not less thanabout 40 mg/dl, not less than about 50 mg/dl, not less than about 60mg/dl, not less than about 70 mg/dl, not less than about 90 mg/dl or notless than about 90 mg/dl.

In a related embodiment, upon treatment in accordance with the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits one or more of the following outcomes:

(a) reduced triglyceride levels compared to baseline or placebo control(e.g. a subject on stable statin plus placebo matching the EPA treatmentgroup);

(b) reduced Apo B levels compared to baseline or placebo control;

(c) a decrease or an increase in HDL-C levels compared to baseline orplacebo control;

(d) no increase in LDL-C levels compared to baseline or placebo control;

(e) a reduction in LDL-C levels compared to baseline or placebo control;

(f) a reduction in non-HDL-C levels compared to baseline or placebocontrol;

(g) a reduction in VLDL-C levels compared to baseline or placebocontrol;

(h) an increase, no change, or a decrease in Apo A-1 levels compared tobaseline or placebo control;

(i) an decrease, no change, or an increase in Apo B/Apo A-1 ratiocompared to baseline or placebo control;

(j) no increase or a reduction in lipoprotein A levels compared tobaseline or placebo control;

(k) a reduction in LDL particle number compared to baseline or placebocontrol;

(l) an increase in LDL size compared to baseline or placebo control;

(m) a reduction in remnant-like particle cholesterol (RLP-C) compared tobaseline or placebo control;

(n) a reduction in oxidized LDL compared to baseline or placebo control;

(o) an increase, no change, or a reduction in fasting plasma glucose(FPG) compared to baseline or placebo control;

(p) an increase, no change, or a reduction in hemoglobin A_(1c)(HbA_(1c)) compared to baseline or placebo control;

(q) an increase, no change, or a reduction in homeostasis model insulinresistance (HOMA-IR) compared to baseline or placebo control;

(r) a reduction in lipoprotein associated phospholipase A2 (Lp-PLA2)compared to baseline or placebo control;

(s) a reduction in intracellular adhesion molecule-1 (IAM-1) compared tobaseline or placebo control;

(t) an increase, no change, or a reduction in interleukin-6 (IL-6)compared to baseline or placebo control;

(u) an increase, no change, or a reduction in plasminogen activatorinhibitor-1 (PAI-1) compared to baseline or placebo control;

(v) a reduction in high sensitivity C-reactive protein (hsCRP) comparedto baseline or placebo control;

(w) an increase in serum or plasma EPA compared to baseline or placebocontrol;

(x) an increase in red blood cell membrane EPA compared to baseline orplacebo control;

(y) a reduction or increase in one or more of serum and/or red bloodcell content of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA),arachidonic acid (AA), palmitic acid (PA), stearidonic acid (SA) oroleic acid (OA) compared to baseline or placebo control;

(z) a reduction in a fatty acid desaturation index (“FADI”) compared tobaseline or placebo control;

(aa) a reduction in VLDL-TG compared to baseline or placebo control;

(bb) a reduction in total cholesterol compared to baseline or placebocontrol; and/or

(cc) an increase, no change, or a reduction in insulin compared tobaseline or placebo control.

In one embodiment, methods of the present invention comprise measuringbaseline levels of one or more markers set forth in (a)-(cc) above priorto dosing the subject or subject group. In another embodiment, themethods comprise administering a composition as disclosed herein to thesubject after baseline levels of one or more markers set forth in(a)-(cc) are determined, and subsequently taking an additionalmeasurement of said one or more markers.

In another embodiment, upon treatment with a composition of the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits any 2 or more of, any 3 or more of,any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of,any 8 or more of, any 9 or more of, any 10 or more of, any 11 or moreof, any 12 or more of, any 13 or more of, any 14 or more of, any 15 ormore of, any 16 or more of, any 17 or more of, any 18 or more of, any 19or more of, any 20 or more of, any 21 or more of, any 22 or more of, any23 or more of, any 24 or more of, any 25 or more of, any 26 or more of,any 27 or more of, any 28 or more of, or all 29 of outcomes (a)-(cc)described immediately above.

In another embodiment, upon treatment with a composition of the presentinvention, the subject or subject group exhibits one or more of thefollowing outcomes:

(a) a reduction in triglyceride level of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55% or at least about 75%(actual % change or median % change) as compared to baseline or placebocontrol (e.g. a subject on statin and placebo matching the EPA treatmentgroup);

(b) a less than 30% increase, less than 20% increase, less than 10%increase, less than 5% increase or no increase in non-HDL-C levels or areduction in non-HDL-C levels of at least about 1%, at least about 3%,at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, at leastabout 55% or at least about 75% (actual % change or median % change) ascompared to baseline or placebo control;

(c) an reduction in HDL-C levels of no greater than about 10%, nogreater than about 5%, no greater than about 4%, no greater than about3%, no greater than about 2%, no greater than about 1%, substantially nochange in HDL-C levels, no change in HDL-C levels, or an increase inHDL-C levels of at least about 5%, at least about 10%, at least about15%, at least about 20%, at least about 25%, at least about 30%, atleast about 35%, at least about 40%, at least about 45%, at least about50%, at least about 55% or at least about 75% (actual % change or median% change) as compared to baseline or placebo control;

(d) a less than 60% increase, a less than 50% increase, a less than 40%a increase, a less than 30% increase, a less than 20% increase, a lessthan 10% increase, a less than 5% increase, a less than 4% increase, aless than 3% increase, a less than 2% increase, in LDL-C levels, noincrease in LDL-C levels, or a reduction in LDL-C levels of at leastabout 3%, at least about 4%, at least about 5%, at least about 6%, atleast about 10%, at least about 15%, at least about 20%, at least about25%, at least about 30%, at least about 35%, at least about 40%, atleast about 45%, at least about 50%, at least about 55%, at least about55% or at least about 75% (actual % change or median % change) ascompared to baseline or placebo control;

(e) an increase in Apo B levels of no more than about 5%, no more thanabout 4%, no more than about 3%, no more than about 2%, no more thanabout 1%, or no increase in Apo B levels, or a decrease in Apo B levelsof at least about 1%, at least about 2%, at least about 3%, at leastabout 4%, at least about 5%, at least about 10%, at least about 15%, atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 45%, at least about 50%, atleast about 55% or at least about 75% (actual % change or median %change) as compared to baseline or placebo control;

(f) an increase in VLDL-C levels of no more than about 5%, no more thanabout 4%, no more than about 3%, no more than about 2%, no more thanabout 1%, no increase in VLDL-C levels, or a reduction in VLDL-C levelsof at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change or median % change) compared to baseline orplacebo control;

(g) an increase in Apo A-1 levels of at least about 1%, at least about2%, at least about 3%, at least about 4%, at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, or at least about 100%, substantially nochange in Apo A-1 levels, no change in Apo A-1 levels, or a reduction inApo A-1 levels of no greater than about 1%, no greater than about 2%, nogreater than about 3%, no greater than about 4%, no greater than about5%, no greater than about 6%, no greater than about 7%, no greater thanabout 8%, no greater than about 9%, or no greater than about 10% (actual% change or median % change) compared to baseline or placebo control;

(h) an increase in Apo B/Apo A-1 ratio of no more than about 5%, no morethan about 4%, no more than about 3%, no more than about 2%, no morethan about 1%, or no more than about 0.5%, no substantial change in inApo B/Apo A-1 ratio, no change in in Apo B/Apo A-1 ratio, or an decreasein Apo B/Apo A-1 ratio of at least about 0.5%, at least about 1%, atleast about 2%, at least about 3%, at least about 4%, at least about 5%,at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, or at least about 100% (actual %change or median % change) compared to baseline or placebo control;

(i) an increase in lipoprotein (a) levels of no more than about 5%, nomore than about 4%, no more than about 3%, no more than about 2%, nomore than about 1%, no more than about 0.5%, no substantial change inlipoprotein (a) levels, no change in lipoprotein (a) levels, or areduction in lipoprotein (a) levels of at least about 0.5%, at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change or median % change) compared to baseline orplacebo control;

(j) an increase in LDL particle number of no more than about 5%, no morethan about 4%, no more than about 3%, no more than about 2%, or no morethan about 1%, no substantial change in LDL particle number, no changein LDL particle number, or a reduction in mean LDL particle number of atleast about 5%, at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change or median % change) compared to baseline orplacebo control;

(k) an increase in mean LDL particle size of at least about0.5%, atleast about 1%, at least about 2%, at least about 3%, at least about 4%,at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change or median % change) compared to baseline orplacebo control;

(l) a reduction in remnant-like particle cholesterol (RLP-C) of at leastabout 5%, at least about 10%, at least about 15%, at least about 20%, atleast about 25%, at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, or at least about 100%(actual % change or median % change) compared to baseline or placebocontrol;

(m) an increase in oxidized LDL of no more than about 5%, no more thanabout 4%, no more than about 3%, no more than about 2%, or no more thanabout 1%, no substantial change in oxidized LDL, no change in LDL, or areduction in oxidized LDL of at least about 1%, at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, or at least about 100% (actual % change ormedian % change) compared to baseline or placebo control;

(n) an increase in fasting plasma glucose (FPG) of no more than about10%, no more than about 9%, no more than about 8%, no more than about7%, no more than about 6%, no more than about 5%, no more than about 4%,no more than about 3%, no more than about 2%, or no more than about 1%,substantially no change, no statistically significant change, or areduction in fasting plasma glucose (FPG) of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, or at least about 100% (actual % changeor median % change) compared to baseline or placebo control;

(o) an increase in hemoglobin A_(1c) (HbA_(1c)) of no more than about2%, no more than about 1%, or no more than about 0.5%, substantially nochange, no statistically significant change, a reduction in hemoglobinA_(1c) (HbA_(1c)) of at least about 5%, at least about 10%, at leastabout 15%, at least about 20%, at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, or at leastabout 50% (actual % change or median % change) compared to baseline orplacebo control;

(p) an increase in homeostasis model index insulin resistance (HOMA-IR)of no more than about 5%, no more than about 4%, no more than about 3%,no more than about 2%, no more than about 1%, or no more than about0.5%, no substantial change in HOMA-IR, no change in HOMA-IR, or areduction in HOMA-IR of at least about 0.1%, at least about 0.5%, atleast about 1%, at least about 2%, at least about 3%, at least about 4%,at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change or median % change) compared to baseline orplacebo control;

(q) a reduction in lipoprotein associated phospholipase A2 (Lp-PLA2) ofat least about 1%, at least about 2%, at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, or at least about 100% (actual % change ormedian % change) compared to baseline or placebo control;

(r) an increase in intracellular adhesion molecule-1 (ICAM-1) of no morethan about 5%, no more than about 4%, no more than about 3%, no morethan about 2%, or no more than about 1%, no substantial change inICAM-1, no change in ICAM-1, or a reduction in ICAM-1 of at least about5%, at least about 10%, at least about 15%, at least about 20%, at leastabout 25%, at least about 30%, at least about 35%, at least about 40%,at least about 45%, at least about 50%, or at least about 100% (actual %change or median % change) compared to baseline or placebo control;

(s) an increase in interleukin-6 (IL-6) of no more than about 5%, nomore than about 4%, no more than about 3%, no more than about 2%, nomore than about 1%, or no more than about 0.5%, no substantial change inIL-6, no change in IL-6, or a reduction in IL-6 of at least about 0.1%,at least about 1%, at least about 2%, at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, or at least about 100% (actual % change ormedian % change) compared to baseline or placebo control;

(t) an increase in plasminogen activator inhibitor-1 (PAI-1) of no morethan about 15%, no more than about 10%, no more than about 5%, or nomore than about 1%, no substantial change in PAI-1, no change in PAI-1,or a reduction in PAI-1 of at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, or at least about 100% (actual % change or median %change) compared to baseline or placebo control;

(u) an increase in high sensitivity C-reactive protein (hsCRP) of nomore than about 15%, no more than about 10%, no more than about 5%, orno more than about 1%, no substantial change in hsCRP, no change inhsCRP, or a reduction in hsCRP of at least about 1%, at least about 2%,at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, at least about 50%, or at leastabout 100% (actual % change or median % change) compared to baseline orplacebo control;

(v) an increase in serum, plasma and/or RBC EPA of at least about 5%, atleast about 10%, at least about 15%, at least about 20%, at least about25%, at least about 30%, at least about 35%, at least about 40%, atleast about 45%, at least about 50%, at least about 100%, at least about200% or at least about 400% (actual % change or median % change)compared to baseline or placebo control;

(w) an increase in serum phospholipid and/or red blood cell membrane EPAof at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, or at least about 50%, at leastabout 100%, at least about 200%, or at least about 400% (actual % changeor median % change) compared to baseline or placebo control;

(x) a reduction or increase in one or more of serum phospholipid and/orred blood cell DHA, DPA, AA, PA and/or OA of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55% or at least about 75%(actual % change or median % change) compared to baseline or placebocontrol;

(y) a reduction in total cholesterol of at least about 5%, at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 55% or at least about 75%(actual % change or median % change) compared to baseline or placebocontrol;

(z) a reduction in a fatty acid desaturation index (“FADI”) of at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about 8%,at least about 9%, at least about 10%, at least about 11%, at leastabout 12%, at least about 13%, at least about 14%, at least about 15%,at least about 20%, at least about 25%, at least about 30%, at leastabout 35%, at least about 40%, at least about 45%, at least about 50%,at least about 55%, at least about 60%, at least about 65%, at leastabout 70%, at least about 75%, at least about 80%, at least about 85%,at least about 90%, at least about 95%, or greater than about 95%(actual % change or median % change) compared to baseline or placebocontrol;

(aa) a reduction in VLDL-TG of at least about 1%, at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 40%, or at least about 50% (actual %change or median % change) compared to baseline or placebo control;

(bb) an increase in total cholesterol of no more than about 5%, no morethan about 4%, no more than about 3%, no more than about 2%, or no morethan about 1%, no substantial change in total cholesterol, no change intotal cholesterol, or a reduction in total cholesterol of at least about2%, at least about 3%, at least about 4%, at least about 5%, at leastabout 6%, at least about 7%, at least about 8%, at least about 9%, atleast about 10%, at least about 11%, at least about 12%, at least about13%, at least about 14%, at least about 15%, or at least about 20%(actual % change or median % change) compared to baseline or placebocontrol; and/or

(cc) an increase in insulin of no more than about 5%, no more than about4%, no more than about 3%, no more than about 2%, no more than about 1%,or no more than about 0.5%, no substantial change in insulin, no changein insulin, or a decrease in insulin of at least about 0.1%, at leastabout 0.5%, at least about 1%, at least about 2%, at least about 3%, atleast about 4%, or at least about 5% (actual % change or median %change) compared to baseline or placebo control.

In one embodiment, methods of the present invention comprise measuringbaseline levels of one or more markers set forth in (a)-(cc) prior todosing the subject or subject group. In another embodiment, the methodscomprise administering a composition as disclosed herein to the subjectafter baseline levels of one or more markers set forth in (a)-(cc) aredetermined, and subsequently taking a second measurement of the one ormore markers as measured at baseline for comparison thereto.

In another embodiment, upon treatment with a composition of the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits any 2 or more of, any 3 or more of,any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of,any 8 or more of, any 9 or more of, any 10 or more of, any 11 or moreof, any 12 or more of, any 13 or more of, any 14 or more of, any 15 ormore of, any 16 or more of, any 17 or more of, any 18 or more of, any 19or more of, any 20 or more of, any 21 or more of, any 22 or more of, any23 or more of, any 24 or more of, any 25 or more of, any 26 or more of,any 27 or more of, any 28 or more of, or all 29 of outcomes (a)-(cc)described immediately above.

Parameters (a)-(z) can be measured in accordance with any clinicallyacceptable methodology. For example, triglycerides, total cholesterol,HDL-C and fasting blood sugar can be sample from serum and analyzedusing standard photometry techniques. VLDL-TG, LDL-C and VLDL-C can becalculated or determined using serum lipoprotein fractionation bypreparative ultracentrifugation and subsequent quantitative analysis byrefractometry or by analytic ultracentrifugal methodology. Apo A1, Apo Band hsCRP can be determined from serum using standard nephelometrytechniques. Lipoprotein (a) can be determined from serum using standardturbidimetric immunoassay techniques. LDL particle number and particlesize can be determined using nuclear magnetic resonance (NMR)spectrometry. Remnants lipoproteins and LDL-phospholipase A2 can bedetermined from EDTA plasma or serum and serum, respectively, usingenzymatic immunoseparation techniques. Oxidized LDL, intercellularadhesion molecule-1 and interleukin-2 levels can be determined fromserum using standard enzyme immunoassay techniques. These techniques aredescribed in detail in standard textbooks, for example TietzFundamentals of Clinical Chemistry, 6^(th) Ed. (Burtis, Ashwood andBorter Eds.), WB Saunders Company.

In one embodiment, subjects fast for up to 12 hours prior to bloodsample collection, for example about 10 hours.

In another embodiment, the subject being treated is in the highest riskcategory of Adult Treatment Panel (ATP) III Classification of LDL,Total, and HDL Cholesterol (mg/dL) (e.g. CHD or CHD Risk Equivalents(10-year risk >20%)). In another embodiment, the subject is in the ATPIII Multiple (2+) risk factor category.

In one embodiment, the invention provides a method of loweringtriglycerides in a subject in the highest risk category of AdultTreatment Panel (ATP) III Classification of LDL, Total, and HDLCholesterol (mg/dL) (e.g. CHD or CHD Risk Equivalents (10-yearrisk >20%)). In another embodiment, the subject is in the ATP IIIMultiple (2+) risk factor category. In another embodiment, the methodincludes a step of identifying a subject in the ATP III Multiple (2+)risk factor category prior to administering ultra-pure E-EPA to thesubject.

In another embodiment, the present invention provides a method oftreating or preventing primary hypercholesterolemia and/or mixeddyslipidemia (Fredrickson Types IIa and IIb) in a patient in needthereof, comprising administering to the patient one or morecompositions as disclosed herein. In a related embodiment, the presentinvention provides a method of reducing triglyceride levels in a subjector subjects when treatment with a statin or niacin extended-releasemonotherapy is considered inadequate (Frederickson type IVhyperlipidemia).

In another embodiment, the present invention provides a method oftreating or preventing risk of recurrent nonfatal myocardial infarctionin a patient with a history of myocardial infarction, comprisingadministering to the patient one or more compositions as disclosedherein.

In another embodiment, the present invention provides a method ofslowing progression of or promoting regression of atheroscleroticdisease in a patient in need thereof, comprising administering to asubject in need thereof one or more compositions as disclosed herein.

In another embodiment, the present invention provides a method oftreating or preventing very high serum triglyceride levels (e.g. TypesIV and V hyperlipidemia) in a patient in need thereof, comprisingadministering to the patient one or more compositions as disclosedherein.

In another embodiment, the present invention provides a method oflowering triglycerides and a fatty acid desaturation index (“FADI”) in asubject on statin therapy having baseline fasting triglycerides of about200 mg/dl to about 500 mg/dl, the method comprising administering to thesubject about 4 capsules per day, each capsule comprising about 1 g ofethyl eicosapentaenoate. In some embodiments, the subject has a baselineLDL-C level of about 40 mg/dl to about 115 mg/dl. In some embodiments,the method effects a reduction in serum LDL-C. In some embodiments, themethod effects at least a 5% reduction in fasting triglycerides and areduction in LDL-C. In some embodiments, the method effects at least a5%, at least a 10%, or at least a 15% reduction in LDL-C. In someembodiments, the method effects at least about 2%, at least about 3%, atleast about 4%, at least about 5%, at least about 6%, at least about 7%,at least about 8%, at least about 9%, at least about 10%, at least about11%, at least about 12%, at least about 13%, at least about 14%, atleast about 15%, at least about 16%, at least about 17%, at least about18%, at least about 19%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, at least about 55%, at least about 60%, atleast about 65%, at least about 70%, at least about 75%, at least about80%, at least about 85%, at least about 90%, at least about 95%, orgreater than about 95% reduction in the FADI (e.g., a ratio ofpalmitoleic acid to palmitic acid and/or a ratio of oleic acid tostearic acid). In some embodiments, the method effects a reduction inApolipoprotein B, total cholesterol, and lipoprotein associatedphospholipase A2. In some embodiments, the subject is on stable statintherapy (e.g., atorvastatin therapy, rosuvastatin therapy, orsimvastatin therapy). In some embodiments, the subject has a baselinebody mass index not greater than 45 kg/m².

In another embodiment, the present invention provides a method oflowering triglycerides, LDL-C and a fatty acid desaturation index(“FADI”) in a subject comprising, administering orally to a subjecthaving fasting triglycerides of about 200 mg/dl to less than 500 mg/dlwho is on stable statin therapy about 4 g per day of a pharmaceuticalcomposition comprising at least about 90%, by weight, of all fatty acids(and/or derivatives thereof) present, ethyl eicosapentaenoate for aperiod of at least about 12 weeks. In some embodiments, the methodeffects a reduction in fasting triglycerides and fasting LDL-C in thesubject compared to fasting triglycerides and fasting LDL-C in a secondsubject on stable statin therapy who has not received the pharmaceuticalcomposition. In some embodiments, the method effects a reduction infasting non-HDL-C compared to fasting non-HDL-C in the second subject.In some embodiments, the method effects a reduction in fasting VLDL-Ccompared to fasting VLDL-C in the second subject. In some embodiments,the method effects a reduction in fasting Apolipoprotein B compared tofasting Apolipoprotein B in the second subject. In some embodiments, themethod effects a reduction in fasting total cholesterol compared tofasting total cholesterol in the second subject. In some embodiments,the method effects at least about 2%, at least about 3%, at least about4%, at least about 5%, at least about 6%, at least about 7%, at leastabout 8%, at least about 9%, at least about 10%, at least about 11%, atleast about 12%, at least about 13%, at least about 14%, at least about15%, at least about 16%, at least about 17%, at least about 18%, atleast about 19%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 55%, at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, at least about 95%, or greater thanabout 95% reduction in the FADI (e.g., a ratio of palmitoleic acid topalmitic acid and/or a ratio of oleic acid to stearic acid).

In one embodiment, a composition of the invention is administered to asubject in an amount sufficient to provide a daily dose of EPA of about1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg,about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, forexample about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg,about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg,about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg,about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg,about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg,about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about2925 mg, about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg,about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg,about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg,about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about3975 mg, about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg,about 4100 mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200mg, about 4225 mg, about 4250 mg, about 4275 mg, about 4300 mg, about4325 mg, about 4350 mg, about 4375 mg, about 4400 mg, about 4425 mg,about 4450 mg, about 4475 mg, about 4500 mg, about 4525 mg, about 4550mg, about 4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg,about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900mg, about 4925 mg, about 4950 mg, about 4975 mg, about 5000 mg, about5025 mg, about 5050 mg, about 5075 mg, about 5100 mg, about 5125 mg,about 5150 mg, about 5175 mg, about 5200 mg, about 5225 mg, about 5250mg, about 5275 mg, about 5300 mg, about 5325 mg, about 5350 mg, about5375 mg, about 5400 mg, about 5425 mg, about 5450 mg, about 5475 mg,about 5500 mg, about 5525 mg, about 5550 mg, about 5575 mg, about 5600mg, about 5625 mg, about 5650 mg, about 5675 mg, about 5700 mg, about5725 mg, about 5750 mg, about 5775 mg, about 5800 mg, about 5825 mg,about 5850 mg, about 5875 mg, about 5900 mg, about 5925 mg, about 5950mg, about 5975 mg, about 6000 mg, about 6025 mg, about 6050 mg, about6075 mg, about 6100 mg, about 6125 mg, about 6150 mg, about 6175 mg,about 6200 mg, about 6225 mg, about 6250 mg, about 6275 mg, about 6300mg, about 6325 mg, about 6350 mg, about 6375 mg, about 6400 mg, about6425 mg, about 6450 mg, about 6475 mg, about 6500 mg, about 6525 mg,about 6550 mg, about 6575 mg, about 6600 mg, about 6625 mg, about 6650mg, about 6675 mg, about 6700 mg, about 6725 mg, about 6750 mg, about6775 mg, about 6800 mg, about 6825 mg, about 6850 mg, about 6875 mg,about 6900 mg, about 6925 mg, about 6950 mg, about 6975 mg, about 7000mg, about 7025 mg, about 7050 mg, about 7075 mg, about 7100 mg, about7125 mg, about 7150 mg, about 7175 mg, about 7200 mg, about 7225 mg,about 7250 mg, about 7275 mg, about 7300 mg, about 7325 mg, about 7350mg, about 7375 mg, about 7400 mg, about 7425 mg, about 7450 mg, about7475 mg, about 7500 mg, about 7525 mg, about 7550 mg, about 7575 mg,about 7600 mg, about 7625 mg, about 7650 mg, about 7675 mg, about 7700mg, about 7725 mg, about 7750 mg, about 7775 mg, about 7800 mg, about7825 mg, about 7850 mg, about 7875 mg, about 7900 mg, about 7925 mg,about 7950 mg, about 7975 mg, about 8000 mg, about 8025 mg, about 8050mg, about 8075 mg, about 8100 mg, about 8125 mg, about 8150 mg, about8175 mg, about 8200 mg, about 8225 mg, about 8250 mg, about 8275 mg,about 8300 mg, about 8325 mg, about 8350 mg, about 8375 mg, about 8400mg, about 8425 mg, about 8450 mg, about 8475 mg, about 8500 mg, about8525 mg, about 8550 mg, about 8575 mg, about 8600 mg, about 8625 mg,about 8650 mg, about 8675 mg, about 8700 mg, about 8725 mg, about 8750mg, about 8775 mg, about 8800 mg, about 8825 mg, about 8850 mg, about8875 mg, about 8900 mg, about 8925 mg, about 8950 mg, about 8975 mg,about 9000 mg, about 9025 mg, about 9050 mg, about 9075 mg, about 9100mg, about 9125 mg, about 9150 mg, about 9175 mg, about 9200 mg, about9225 mg, about 9250 mg, about 9275 mg, about 9300 mg, about 9325 mg,about 9350 mg, about 9375 mg, about 9400 mg, about 9425 mg, about 9450mg, about 9475 mg, about 9500 mg, about 9525 mg, about 9550 mg, about9575 mg, about 9600 mg, about 9625 mg, about 9650 mg, about 9675 mg,about 9700 mg, about 9725 mg, about 9750 mg, about 9775 mg, about 9800mg, about 9825 mg, about 9850 mg, about 9875 mg, about 9900 mg, about9925 mg, about 9950 mg, about 9975 mg, or about 10,000 mg.

In another embodiment, any of the methods disclosed herein are used intreatment of a subject or subjects that consume a traditional Westerndiet. In one embodiment, the methods of the invention include a step ofidentifying a subject as a Western diet consumer or prudent dietconsumer and then treating the subject if the subject is deemed aWestern diet consumer. The term “Western diet” herein refers generallyto a typical diet consisting of, by percentage of total calories, about45% to about 50% carbohydrate, about 35% to about 40% fat, and about 10%to about 15% protein. A Western diet may alternately or additionally becharacterized by relatively high intakes of red and processed meats,sweets, refined grains, and desserts, for example more than 50%, morethan 60% or more or 70% of total calories come from these sources.

In another embodiment, any of the methods disclosed herein are used intreatment of a subject or subjects that consume less than (actual oraverage) about 150 g, less than about 125 g, less than about 100 g, lessthan about 75 g, less than about 50 g, less than about 45 g, less thanabout 40 g, less than about 35 g, less than about 30 g, less than about25 g, less than about 20 g or less than about 15 g of fish per day.

In another embodiment, any of the methods disclosed herein are used intreatment of a subject or subjects that consume less than (actual oraverage) about 10 g, less than about 9 g, less than about 8 g, less thanabout 7 g, less than about 6 g, less than about 5 g, less than about 4g, less than about 3 g, less than about 2 g per day of omega-3 fattyacids from dietary sources.

In another embodiment, any of the methods disclosed herein are used intreatment of a subject or subjects that consume less than (actual oraverage) about 2.5 g, less than about 2 g, less than about 1.5 g, lessthan about 1 g, less than about 0.5 g, less than about 0.25 g, or lessthan about 0.2 g per day of EPA and DHA (combined) from dietary sources.

In one embodiment, compositions useful in various embodiments of theinvention comprise a polyunsaturated fatty acid as an active ingredient.In another embodiment, such compositions comprise EPA as an activeingredient. The term “EPA” as used herein refers to eicosapentaenoicacid (e.g. eicosa-5,8,11,14,17-pentaenoic acid) and/or apharmaceutically acceptable ester, derivative, conjugate or saltthereof, or mixtures of any of the foregoing.

In one embodiment, the EPA comprises all-ciseicosa-5,8,11,14,17-pentaenoic acid. In another embodiment, the EPA isin the form of an eicosapentaenoic acid ester. In another embodiment,the EPA comprises a C₁-C₅ alkyl ester of EPA. In another embodiment, theEPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acidmethyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoicacid butyl ester. In still another embodiment, the EPA comprises all-ciseicosa-5,8,11,14,17-pentaenoic acid ethyl ester.

In still other embodiments, the EPA comprises ethyl-EPA, lithium EPA,mono, di- or triglyceride EPA or any other ester or salt of EPA, or thefree acid form of EPA. The EPA may also be in the form of a2-substituted derivative or other derivative which slows down its rateof oxidation but does not otherwise change its biological action to anysubstantial degree.

The term “pharmaceutically acceptable” in the present context means thatthe substance in question does not produce unacceptable toxicity to thesubject or interaction with other components of the composition.

In one embodiment, EPA present in a composition suitable for useaccording to the invention comprises ultra-pure EPA. The term“ultra-pure” as used herein with respect to EPA refers to a compositioncomprising at least 96%, by weight, of all fatty acids (and/orderivatives thereof) present, EPA (as the term “EPA” is defined andexemplified herein). Ultra-pure EPA can comprise even higher purity EPA,for example at least 97%, at least 98%, or at least 99%, by weight, ofall fatty acids (and/or derivatives thereof) present, EPA, wherein theEPA is any form of EPA as set forth herein. Ultra-pure EPA can furtherbe defined (e.g. impurity profile) by any of the description of EPAprovided herein.

In some embodiments, EPA is present in a composition in an amount ofabout 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg,about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg,about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg,about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg,about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg,about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg,about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg,about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg,about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about3925 mg, about 3950 mg, about 3975 mg, about 4000 mg, about 4025 mg,about 4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about 4150mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg, about4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg,about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about 4500mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg, about4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg,about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about4975 mg, or about 5000 mg.

In various embodiments, one or more antioxidants can be present in theEPA (e.g. E-EPA or ultra pure E-EPA). Non-limiting examples of suitableantioxidants include tocopherol, lecithin, citric acid and/or ascorbicacid. One or more antioxidants, if desired, are typically present in theEPA in an amount of about 0.01% to about 0.1%, by weight, or about0.025% to about 0.05%, by weight.

In one embodiment, a composition of the invention contains not more thanabout 10%, not more than about 9%, not more than about 8%, not more thanabout 7%, not more than about 6%, not more than about 5%, not more thanabout 4%, not more than about 3%, not more than about 2%, not more thanabout 1%, or not more than about 0.5%, by weight, of all fatty acids(and/or derivatives thereof) present, docosahexaenoic acid or derivativethereof such as E-DHA, if any. In another embodiment, a composition ofthe invention contains substantially no docosahexaenoic acid orderivative thereof such as E-DHA. In still another embodiment, acomposition of the invention contains no docosahexaenoic acid or E-DHA.

In another embodiment, EPA represents at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 95%, atleast about 97%, at least about 98%, at least about 99%, or 100%, byweight, of all fatty acids (and/or derivatives thereof) present in acomposition useful in accordance with the invention.

In another embodiment, a composition of the invention contains less than30%, less than 20%, less than 10%, less than 9%, less than 8%, less than7%, less than 6%, less than 5%, less than 4%, less than 3%, less than2%, less than 1%, less than 0.5% or less than 0.25%, by weight of thetotal composition or by weight of the total fatty acid content(including or excluding derivatives of fatty acids), of any fatty acidother than EPA, or derivative thereof. Illustrative examples of a “fattyacid other than EPA” include linolenic acid (LA) or derivative thereofsuch as ethyl-linolenic acid, arachidonic acid (AA) or derivativethereof such as ethyl-AA, docosahexaenoic acid (DHA) or derivativethereof such as ethyl-DHA, alpha-linolenic acid (ALA) or derivativethereof such as ethyl-ALA, stearadonic acid (STA) or derivative thereofsuch as ethyl-SA, eicosatrienoic acid (ETA) or derivative thereof suchas ethyl-ETA and/or docosapentaenoic acid (DPA) or derivative thereofsuch as ethyl-DPA.

In another embodiment, a composition of the invention has one or more ofthe following features: (a) eicosapentaenoic acid ethyl ester representsat least 96%, at least 97%, or at least 98%, by weight, of all fattyacids (and/or derivatives thereof) present in the composition; (b) thecomposition contains not more than 4%, not more than 3%, or not morethan 2%, by weight, of all fatty acids (and/or derivatives thereof)present, of fatty acids other than eicosapentaenoic acid ethyl ester;(c) the composition contains not more than 0.6%, 0.5%, 0.4% or 0.3%, byweight, of all fatty acids (and/or derivatives thereof) present, of anyindividual fatty acid other than eicosapentaenoic acid ethyl ester; (d)the composition has a refractive index (20° C.) of about 1 to about 2,about 1.2 to about 1.8 or about 1.4 to about 1.5; (e) the compositionhas a specific gravity (20° C.) of about 0.8 to about 1.0, about 0.85 toabout 0.95 or about 0.9 to about 0.92; (f) the composition contains notmore than 20 ppm, 15 ppm or 10 ppm heavy metals, (g) the compositioncontains not more than 5 ppm, 4 ppm, 3 ppm, or 2 ppm arsenic, and/or (h)the composition has a peroxide value not more than 5, 4, 3, or 2 Meq/kg.

In another embodiment, a composition useful in accordance with theinvention comprises, consists essentially of or consists of at least95%, by weight, of all fatty acids (and/or derivatives thereof) present,ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5%, by weight, ofall fatty acids (and/or derivatives thereof) present, ethyloctadecatetraenoate (ODTA-E), about 0.05% to about 0.25%, by weight, ofall fatty acids (and/or derivatives thereof) present, ethylnonadecapentaenoate (NDPA-E), about 0.2% to about 0.45%, by weight, ofall fatty acids (and/or derivatives thereof) present, ethyl arachidonate(AA-E), about 0.3% to about 0.5%, by weight, of all fatty acids (and/orderivatives thereof) present, ethyl eicosatetraenoate (ETA-E), and about0.05% to about 0.32%, by weight, of all fatty acids (and/or derivativesthereof) present, ethyl heneicosapentaenoate (HPA-E). In anotherembodiment, the composition is present in a capsule shell. In stillanother embodiment, the capsule shell contains no chemically modifiedgelatin.

In another embodiment, compositions useful in accordance with theinvention comprise, consist essentially of, or consist of at least 95%,96% or 97%, by weight, of all fatty acids (and/or derivatives thereof)present, ethyl eicosapentaenoate, about 0.2% to about 0.5%, by weight,of all fatty acids (and/or derivatives thereof) present, ethyloctadecatetraenoate, about 0.05% to about 0.25%, by weight, of all fattyacids (and/or derivatives thereof) present, ethyl nonadecapentaenoate,about 0.2% to about 0.45%, by weight, of all fatty acids (and/orderivatives thereof) present, ethyl arachidonate, about 0.3% to about0.5%, by weight, of all fatty acids (and/or derivatives thereof)present, ethyl eicosatetraenoate, and about 0.05% to about 0.32%, byweight, of all fatty acids (and/or derivatives thereof) present, ethylheneicosapentaenoate. Optionally, the composition contains not more thanabout 0.06%, about 0.05%, or about 0.04%, by weight, of all fatty acids(and/or derivatives thereof) present, DHA or derivative thereof such asethyl-DHA. In one embodiment the composition contains substantially noor no amount of DHA or derivative thereof such as ethyl-DHA. Thecomposition further optionally comprises one or more antioxidants (e.g.tocopherol) in an amount of not more than about 0.5% or not more than0.05%. In another embodiment, the composition comprises about 0.05% toabout 0.4%, for example about 0.2% by weight tocopherol. In anotherembodiment, about 500 mg to about 1 g of the composition is provided ina capsule shell. In another embodiment, the capsule shell contains nochemically modified gelatin.

In another embodiment, compositions useful in accordance with theinvention comprise, consist essentially of, or consist of at least 96%,by weight, of all fatty acids (and/or derivatives thereof) present,ethyl eicosapentaenoate, about 0.22% to about 0.4%, by weight, of allfatty acids (and/or derivatives thereof) present, ethyloctadecatetraenoate, about 0.075% to about 0.20%, by weight, of allfatty acids (and/or derivatives thereof) present, ethylnonadecapentaenoate, about 0.25% to about 0.40%, by weight, of all fattyacids (and/or derivatives thereof) present, ethyl arachidonate, about0.3% to about 0.4%, by weight, of all fatty acids (and/or derivativesthereof) present, ethyl eicosatetraenoate and about 0.075% to about0.25%, by weight, of all fatty acids (and/or derivatives thereof)present, ethyl heneicosapentaenoate. Optionally, the compositioncontains not more than about 0.06%, about 0.05%, or about 0.04%, byweight, of all fatty acids (and/or derivatives thereof) present, DHA orderivative thereof such as ethyl-DHA. In one embodiment the compositioncontains substantially no or no amount of DHA or derivative thereof suchas ethyl-DHA. The composition further optionally comprises one or moreantioxidants (e.g. tocopherol) in an amount of not more than about 0.5%or not more than 0.05%. In another embodiment, the composition comprisesabout 0.05% to about 0.4%, for example about 0.2% by weight tocopherol.In another embodiment, the invention provides a dosage form comprisingabout 500 mg to about 1 g of the foregoing composition in a capsuleshell. In one embodiment, the dosage form is a gel- or liquid-containingcapsule and is packaged in blister packages of about 1 to about 20capsules per sheet.

In another embodiment, compositions useful in accordance with theinvention comprise, consist essentially of or consist of at least 96%,97% or 98%, by weight, of all fatty acids (and/or derivatives thereof)present, ethyl eicosapentaenoate, about 0.25% to about 0.38%, by weight,of all fatty acids (and/or derivatives thereof) present, ethyloctadecatetraenoate, about 0.10% to about 0.15%, by weight, of all fattyacids (and/or derivatives thereof) present, ethyl nonadecapentaenoate,about 0.25% to about 0.35%, by weight, of all fatty acids (and/orderivatives thereof) present, ethyl arachidonate, about 0.31% to about0.38% by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20%,by weight, of all fatty acids (and/or derivatives thereof) present,ethyl heneicosapentaenoate. Optionally, the composition contains notmore than about 0.06%, about 0.05%, or about 0.04%, by weight, of allfatty acids (and/or derivatives thereof) present, DHA or derivativethereof such as ethyl-DHA. In one embodiment the composition containssubstantially no or no amount of DHA or derivative thereof such asethyl-DHA. The composition further optionally comprises one or moreantioxidants (e.g. tocopherol) in an amount of not more than about 0.5%or not more than 0.05%. In another embodiment, the composition comprisesabout 0.05% to about 0.4%, for example about 0.2% by weight tocopherol.In another embodiment, the invention provides a dosage form comprisingabout 500 mg to about 1 g of the foregoing composition in a capsuleshell. In another embodiment, the capsule shell contains no chemicallymodified gelatin.

In another embodiment, a composition as described herein is administeredto a subject once or twice per day. In another embodiment, 1, 2, 3 or 4capsules, each containing about 1 g of a composition as describedherein, are administered to a subject daily. In another embodiment, 1 or2 capsules, each containing about 1 g of a composition as describedherein, are administered to the subject in the morning, for examplebetween about 5 am and about 11 am, and 1 or 2 capsules, each containingabout 1 g of a composition as described herein, are administered to thesubject in the evening, for example between about 5 pm and about 11 pm.

In one embodiment, a subject being treated in accordance with methods ofthe invention is not on fibrate or nitrate therapy.

In another embodiment, compositions useful in accordance with methods ofthe invention are orally deliverable. The terms “orally deliverable” or“oral administration” herein include any form of delivery of atherapeutic agent or a composition thereof to a subject wherein theagent or composition is placed in the mouth of the subject, whether ornot the agent or composition is swallowed. Thus “oral administration”includes buccal and sublingual as well as esophageal administration. Inone embodiment, the composition is present in a capsule, for example asoft gelatin capsule.

A composition for use in accordance with the invention can be formulatedas one or more dosage units. The terms “dose unit” and “dosage unit”herein refer to a portion of a pharmaceutical composition that containsan amount of a therapeutic agent suitable for a single administration toprovide a therapeutic effect. Such dosage units may be administered oneto a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) oftimes per day, or as many times as needed to elicit a therapeuticresponse.

In another embodiment, the invention provides use of any compositiondescribed herein for treating moderate to severe hypertriglyceridemia ina subject in need thereof, comprising: providing a subject having afasting baseline triglyceride level of about 500 mg/dl to about 1500mg/dl and administering to the subject a pharmaceutical composition asdescribed herein. In one embodiment, the composition comprises about 1 gto about 4 g of eicosapentaenoic acid ethyl ester, wherein thecomposition contains substantially no docosahexaenoic acid.

EXAMPLES Example 1 Safety and Efficacy of Ultra-Pure EPA

A multi-center, placebo-controlled, randomized, double-blind, 12-weekstudy was performed to evaluate the efficacy and safety of >96% E-EPA inpatients with fasting triglyceride levels ≥200 mg/dl and <500 mg/dldespite statin therapy (the mean of two qualifying entry values neededto be ≥185 mg/dl and at least one of the values needed to be ≥200mg/dl). The primary objective of the study was to determine the efficacyof >96% E-EPA 2 g daily and 4 g daily, compared to placebo, in loweringfasting TG levels in patients with high risk for cardiovascular diseaseand with fasting TG levels 200 mg/dl and <500 mg/dl, despite treatmentto LDL-C goal on statin therapy.

The secondary objectives of this study were the following:

-   -   1. To determine the safety and tolerability of >96% E-EPA 2 g        daily and 4 g daily;    -   2. To determine the effect of >96% E-EPA on lipid and        apolipoprotein profiles including total cholesterol (TC),        non-high-density lipoprotein cholesterol (non-HDL-C), low        density lipoprotein cholesterol (LDL-C), high density        lipoprotein cholesterol (HDL-C), and very high density        lipoprotein cholesterol (VHDL-C);    -   3. To determine the effect of >96% E-EPA on lipoprotein        associated phospholipase A₂ (Lp-PLA2) from baseline to week 12;    -   4. To determine the effect of >96% E-EPA on low-density        lipoprotein (LDL) particle number and size;    -   5. To determine the effect of >96% E-EPA on oxidized LDL;    -   6. To determine the effect of >96% E-EPA on fasting plasma        glucose (FPG) and hemoglobin A_(1c) (HbA_(1c));    -   7. To determine the effect of >96% E-EPA on insulin resistance;    -   8. To determine the effect of >96% E-EPA on high-sensitivity        C-reactive protein (hsCRP);    -   9. To determine the effects of >96% E-EPA 2 g daily and 4 g        daily on the incorporation of fatty acids into red blood cell        membranes and into plasma phospholipids;    -   10. To explore the relationship between baseline fasting TG        levels and the reduction in fasting TG levels; and    -   11. To explore the relationship between changes of fatty acid        concentrations in plasma and red blood cell membranes, and the        reduction in fasting TG levels.

The population for this study was men and women >18 years of age with abody mass index 45 kg/m² with fasting TG levels greater than or equal to200 mg/dl and less than 500 mg/dl and on a stable does of statin therapy(with or without ezetimibe). The statin was atorvostatin, rosuvastatinor simvastatin. The dose of statin must have been stable for ≥4 weeksprior to the LDL-C/TG baseline qualifying measurement for randomization.The statin dose was optimized such that the patients are at their LDL-Cgoal at the LDL-C/TG baseline qualifying measurements. The same statinat the same dose was continued until the study ended.

Patients taking any additional non-statin, lipid-altering medications(niacin>200 mg/day, fibrates, fish oil, other products containingomega-3 fatty acids, or other herbal products or dietary supplementswith potential lipid-altering effects), either alone or in combinationwith statin therapy (with or without ezetimibe), must have been able tosafely discontinue non-statin, lipid-altering therapy at screening.

Patients at high risk for CVD, i.e., patients with clinical coronaryheart disease (CHD) or clinical CHD risk equivalents (10-year risk>20%)as defined in the National Cholesterol Education Program (NCEP) AdultTreatment Panel III (ATP III) Guidelines were eligible to participate inthis study. Those included patients with any of the following criteria:(1) Known CVD, either clinical coronary heart disease (CHD), symptomaticcarotid artery disease (CAD), peripheral artery disease (PAD) orabdominal aortic aneurism; or (2) Diabetes Mellitus (Type 1 or 2).

Approximately 702 patients were randomized at approximately 80 centersin the U.S. The study was a 18- to 20-week, Phase 3, multi-center studyconsisting of 2 study periods: (1) A 6- to 8-week screening period thatincluded a diet and lifestyle stabilization, a non-statin lipid-alteringtreatment washout, and an LDL-C and TG qualifying period and (2) A12-week, double-blind, randomized, placebo-controlled treatment period.

During the screening period and double-blind treatment period, allvisits were within ±3 days of the scheduled time. All patients continuedto take the statin product (with or without ezetimibe) at the same dosethey were taking at screening throughout their participation in thestudy.

The 6- to 8-week screening period included a diet and lifestylestabilization, a non-statin lipid-altering treatment washout, and anLDL-C and TG qualifying period. The screening visit (Visit 1) occurredfor all patients at either 6 weeks (for patients on stable statintherapy [with or without ezetimibe] at screening) or 8 weeks (forpatients who will require washout of their current non-statinlipid-altering therapy at screening) before randomization, as follows:

-   -   Patients who did not require a washout: The screening visit        occurred at Visit 1 (Week -6). Eligible patients entered a        4-week diet and lifestyle stabilization period. At the screening        visit, all patients received counseling regarding the importance        of the National Cholesterol Education Program (NCEP) Therapeutic        Lifestyle Changes (TLC) diet and received basic instructions on        how to follow this diet.    -   Patients who required a washout: The screening visit occurred at        Visit 1 (Week −8). Eligible patients began a 6-week washout        period at the screening visit (i.e. 6 weeks washout before the        first LDL-C/TG qualifying visit). Patients received counseling        regarding the NCEP TLC diet and received basic instructions on        how to follow this diet. Site personnel contacted patients who        did not qualify for participation based on screening laboratory        test results to instruct them to resume their prior        lipid-altering medications.

At the end of the 4-week diet and lifestyle stabilization period or the6-week diet and stabilization and washout period, eligible patientsentered the 2-week LDL-C and TG qualifying period and had their fastingLDL-C and TG levels measured at Visit 2 (Week −2) and Visit 3 (Week −1).Eligible patients must have had an average fasting LDL-C level >40 mg/dLand <100 mg/dL and an average fasting TG level 200 mg/dL and <500 mg/dLto enter the 12-week double-blind treatment period. The LDL-C and TGlevels for qualification were based on the average (arithmetic mean) ofthe Visit 2 (Week −2) and Visit 3 (Week −1) values. If a patient'saverage LDL-C and/or TG levels from Visit 2 and Visit 3 fell outside therequired range for entry into the study, an additional fasting lipidprofile was collected 1 week later at Visit 3.1. If a third sample wascollected at Visit 3.1, entry into the study was based on the average(arithmetic mean) of the values from Visit 3 and Visit 3.1.

After confirmation of qualifying fasting LDL-C and TG values, eligiblepatients entered a 12-week, randomized, double-blind treatment period.At Visit 4 (Week 0), patients were randomly assigned to 1 of thefollowing treatment groups:

-   -   >96% E-EPA 2 g daily,    -   >96% E-EPA 4 g daily, or    -   Placebo.

226 to 234 patients per treatment group were randomized in this study.Stratification was by type of statin (atorvastatin, rosuvastatin orsimvastatin), the presence of diabetes, and gender.

During the double-blind treatment period, patients returned to the siteat Visit 5 (Week 4), Visit 6 (Week 11), and Visit 7 (Week 12) forefficacy and safety evaluations.

Eligible patients were randomly assigned at Visit 4 (Week 0) to receiveorally >96% E-EPA 2 g daily, >96% E-EPA 4 g daily, or placebo.

>96% E-EPA was provided in 1 g liquid-filled, oblong, gelatin capsules.The matching placebo capsule was filled with light liquid paraffin andcontained 0 g of >96% E-EPA. >96% E-EPA capsules were to be taken withfood (i.e. with or at the end of a meal).

During the double-blind treatment period, patients were to take 2capsules (>96% E-EPA or matching placebo) in the morning and 2 capsulesin the evening for a total of 4 capsules per day.

-   -   Patients in the >96% E-EPA 2 g/day treatment group received        1 >96% E-EPA 1 g capsule and 1 matching placebo capsule in the        morning and in the evening.    -   Patients in the >96% E-EPA 4 g/day treatment group received        2 >96% E-EPA 1 g capsules in the morning and evening.

Patients in the placebo group received 2 matching placebo capsules inthe morning and evening.

The primary efficacy variable for the double-blind treatment period waspercent change in TG from baseline to Week 12 endpoint. The secondaryefficacy variables for the double-blind treatment period included thefollowing:

-   -   Percent changes in total cholesterol (TC), high-density        lipoprotein cholesterol (HDL-C), LDL-C, calculated non-HDL-C,        and very low-density lipoprotein cholesterol (VLDL-C) from        baseline to Week 12 endpoint;    -   Percent change in very low-density lipoprotein TG from baseline        to Week 12;    -   Percent changes in apolipoprotein A-I (Apo A-1), apolipoprotein        B (Apo B), and Apo A-1/Apo B ratio from baseline to Week 12;    -   Percent changes in lipoprotein (a) from baseline to Week 12;    -   Percent changes in LDL particle number and size, measured by        nuclear magnetic resonance, from baseline to Week 12;    -   Percent change in remnant-like particle cholesterol from        baseline to Week 12;    -   Percent change in oxidized LDL from baseline to Week 12;    -   Changes in FPG and HbA_(1c) from baseline to Week 12;    -   Change in insulin resistance, as assessed by the homeostasis        model index insulin resistance, from baseline to Week 12;    -   Percent change in lipoprotein associated phospholipase A₂        (Lp-PLA2) from baseline to Week 12;    -   Change in intracellular adhesion molecule-1 from baseline to        Week 12;    -   Change in interleukin-2 from baseline to Week 12;    -   Change in plasminogen activator inhibitor-1 from baseline to        Week 12. Note: this parameter will only be collected at sites        with proper storage conditions;    -   Change in hsCRP from baseline to Week 12; and    -   Change in plasma concentration and red blood cell membrane        content of fatty acid from baseline to Week 12 including EPA,        docosapentaenoic acid (DPA), docosahexaenoic acid (DHA),        arachidonic acid (AA), dihomo-γ-linolenic acid (DGLA), the ratio        of EPA/AA, ratio of oleic acid/stearic acid (OA/SA), and the        ratio of total omega-3 acids over total omega-6 acids.

Safety assessments included adverse events, clinical laboratorymeasurements (chemistry, hematology, and urinalysis), 12-leadelectrocardiograms (ECGs), vital signs, and physical examinations.

For TG, TC, HDL-C, LDL-C, calculated non-HDL-C, and VLDL-C, baseline wasdefined as the average of Visit 4 (Week 0) and the preceding lipidqualifying visit (either Visit 3 [Week −1] or if it occurs, Visit 3.1)measurements. Baseline for all other efficacy parameters was the Visit 4(Week 0) measurement.

For TG, TC, HDL-C, LDL-C, calculated non-HDL-C, and VLDL-C, Week 12endpoint was defined as the average of Visit 6 (Week 11) and Visit 7(Week 12) measurements.

Week 12 endpoint for all other efficacy parameters were the Visit 7(Week 12) measurement.

The primary efficacy analysis was performed using a 2-way analysis ofcovariance (ANCOVA) model with treatment as a factor and baseline TGvalue as a covariate. The least-squares mean, standard error, and2-tailed 95% confidence interval for each treatment group and for eachcomparison were estimated. The same 2-way ANCOVA model was used for theanalysis of secondary efficacy variables.

The primary analysis was repeated for the per-protocol population toconfirm the robustness of the results for the intent-to-treatpopulation.

Non-inferiority tests for percent change from baseline in LDL-C wereperformed between >96% E-EPA doses and placebo using a non-inferioritymargin of 6% and a significant level at 0.05.

For the following key secondary efficacy parameters, treatment groupswere compared using Dunnett's test to control the Type 1 error rate: TC,LDL-C, HDL-C, non-HDL-C, VLDL-C, Lp-PLA₂, and Apo B. For the remainingsecondary efficacy parameters, Dunnett's test was be used and the ANCOVAoutput were considered descriptive.

The evaluation of safety was based primarily on the frequency of adverseevents, clinical laboratory assessments, vital signs, and 12-lead ECGs.The primary efficacy variable is the percent change in fasting TG levelsfrom baseline to Week 12. A sample size of 194 completed patients pertreatment group provided 90.6% power to detect a difference of 15%between >96% E-EPA and placebo in percent change from baseline infasting TG levels, assuming a standard deviation of 45% in TGmeasurements and a significance level of p<0.05.

Previous data on fasting LDL-C show a difference in percent change frombaseline of 2.2%, with a standard deviation of 15%, between study drugand placebo. A sample size of 194 completed patients per treatment groupprovided 80% power to demonstrate non-inferiority (p<0.05, one-sided) ofthe LDL-C response between >96% E-EPA 4 g daily and placebo, within a 6%margin. To accommodate a 10% drop-out rate from randomization tocompletion of the double-blind treatment period, a total of 648randomized patients was planned (216 patients per treatment group); 702subjects were randomized, as further described below.

Results

Of the 702 randomized subjects, 687 were in the intent-to-treat (“ITT”)population as follows:

-   -   Ultra-pure EPA, 4 g/day: 226 subjects    -   Ultra-pure EPA, 2 g/day: 234 subjects    -   Placebo: 227 subjects

Lipids were extracted from plasma and red blood cell (“RBC”) suspensionsand converted into fatty acid methyl esters for analysis using astandard validated gas chromatography/flame ionization detection method.Fatty acid parameters were compared between EPA treatment groups andplacebo using an ANCOVA model with treatment, gender, type of statintherapy, and presence of diabetes as factors, and the baseline parametervalue as a covariate. LSMs, SEs, and 2-tailed 95% confidence intervalsfor each treatment group and for each comparison were determined.

Baseline characteristics of the three ITT groups were comparable, with61.4% of the ITT subjects being male, 96.3% being white, having a meanage of 61.4 years, a weight of 95.7 kg and a BMI of 32.9 kg/m². ITTsubjects with incomplete fatty acid data at baseline and/or at 12 weekswere excluded from the analyses described below.

As shown in Table 1 below, administration of 4 g per day of ethyleicosapentaenoate (e.g., in a composition according to the presentdisclosure) reduced median concentrations of total VLDL by 12.2% overbaseline when adjusted for placebo (P<0.001). Similarly, medianconcentrations of total LDL were reduced by 7.7% over baseline whenadjusted for placebo (P<0.01). Median concentrations of total HDL werealso reduced, by 7.4% over baseline when adjusted for placebo(P<0.0001). In addition, median concentrations of small LDL particleswere reduced by 13.5% over baseline when adjusted for placebo control(P<0.0001).

TABLE 1 Placebo-Adjusted Effects of 4 g/day Ethyl Eicosapentaenoate onSelect Lipid Parameters Relative to Baseline. Parameter % Change P VLDL−12.2% <0.001 LDL −7.7% <0.01 HDL −7.4% <0.0001 Small LDL −13.5% <0.0001

Additional lipoprotein particle concentration data for 4 g/day and 2g/day ethyl eicosapentaenoate groups is shown in Table 2.

TABLE 2 Median Change from Baseline to Study End in Lipoprotein ParticleConcentrations IPE 4 g/day (n = 216) IPE 2 g/day (n = 222) Placebo (n =211) Median Change Change Change Change From Baseline from from from IPE4 IPE 2 End of Base- End of Base- End of Base- g/day vs g/day vs Base-Treat- line Base- Treat- line Base- Treat- line Placebo Placebo linement % line ment % line ment % %, P %, P Total VLDL, 116.7 110.0 −2.5113.4 122.4 12.0 111.2 122.0 7.9 −12.2 1.8 nmol/L (66.6) (78.0) (41.8)(53.5) (66.2) (56.1) (50.6) (60.0) (40.1) 0.0002 0.6102 Large VLDL, 12.97.7 −41.9 12.1 10.0 −19.7 12.9 14.1 6.0 −46.4 −24.2 nmol/L (10.7) (7.6)(57.2) (8.3) (9.9) (72.5) (9.7) (13.2) (101.1) <0.0001 <0.0001 MediumVLDL, 54.8 49.7 −6.9 52.6 59.6 7.9 53.3 58.8 9.2 −12.1 2.6 nmol/L (37.2)(41.8) (59.3) (33.4) (39.0) (69.6) (29.9) (36.1) (56.3) 0.0068 0.5998Small VLDL, 43.9 46.8 8.3 43.1 49.6 22.1 41.4 45.3 8.5 2.8 16.5 nmol/L(36.8) (39.9) (81.8) (34.8) (41.3) (96.3) (32.8) (37.4) (70.0) 0.63210.0058 Total LDL, 1131 1191 3.8 1171 1215 4.7 1152 1287 11.9 −7.7 −7.5nmol/L (369.5) (512.0) (31.8) (349.0) (355.0) (29.2) (353.0) (456.0)(31.6) 0.0017 0.0013 IDL, nmol/L 51.5 63.0 23.7 45.0 63.5 10.5 55.0 55.00.0 10.0 8.6 (81.5 (94.0) (173.7) (94.0) (122.0) (200.7) (88.0) (102.0)(194.8) 0.3051 0.3602 Large LDL, 113.5 172.5 55.2 128.0 202.0 47.7 113.0166.0 30.6 34.2 26.5 nmol/L (198.5) (226.0) (241.0) (190.0) (242.0)(207.2) (215.0) (271.0) (200.4) 0.0076 0.0336 Small LDL, 894.0 902.5−1.1 944.0 920.5 −4.3 902.0 978.0 11.0 −13.5 −14.7 nmol/L (266.5)(387.5) (36.1) (310.0) (313.0) (32.0) (323.0) (387.0) (39.0) <0.0001<0.0001 Total HDL, 34.3 32.6 −4.0 34.3 34.7 0.7 34.8 35.5 4.7 −7.4 −3.1nmol/L (8.9) (8.2) (16.4) (8.3) (7.2) (14.9) (10.1) (9.3) (16.2) <0.00010.0150 Large HDL, 2.5 1.9 −21.6 2.5 2.4 −4.0 2.8 2.9 9.1 −31.0 −13.5μmol/L (1.8) (2.0) (58.1) (2.0) (2.3) (63.3) (2.0) (2.3) (50.4) <0.00010.0017 Medium HDL, 6.7 6.9 4.2 7.0 7.2 2.9 7.8 8.3 8.6 −6.5 −4.5 μmol/L(6.0) (4.8) (69.4) (5.6) (5.2) (93.8) (5.6) (7.3) (81.8) 0.2245 0.4359Small HDL, 24.2 23.1 −3.9 24.0 23.8 −0.6 23.0 24.0 1.6 −2.8 −0.2 μmol/L(6.4) (6.7) (21.9) (6.7) (6.4) (24.8) (8.1) (7.4) (25.4) 0.1267 0.9028Data are presented as median (IQR) for end point values. Medianplacebo-adjusted percent changes are Hodges-Lehmann medians.

These data show that 4 g/day ethyl eicosapentaenoate significantlyreduced median concentrations of total, large, and medium VLDLparticles; total and small LDL particles; and total and large HDLparticles. In addition, 4 g/day of ethyl eicosapentaenoate increased theconcentration of large LDL particles compared to placebo.

As shown in FIG. 1, atherogenic lipoprotein particle (i.e., total VLDLand total LDL particles) concentrations correlated well with Apo B(N=649; R²=0.64; P<0.0001) at week 12. The shaded band corresponds toconfidence limits of the mean, which is shown as a dark line.

Median changes in lipoprotein particle size from baseline are shown inTable 3 below for 4 g/day ethyl eicosapentaenoate, 2 g/day ethyleicosapentaenoate, and placebo, along with placebo-adjusted medianpercent changes from baseline for both 4 g/day and 2 g/day ethyl-EPAdosages. Data is presents as median (IQR) for end point values, and asHodges-Lehmann medians for placebo-adjusted percent changes.

TABLE 3 Median Change from Baseline to Study End in Lipoprotein ParticleSizes Placebo-Adjusted Median Change from Baseline 4 g/day E-EPA (n =216) 2 g/day E-EPA (n = 222) Placebo (n = 211) 4 g/d, 2 g/d, BaselineEnd % Δ Baseline End % Δ Baseline End % Δ %, P %, P VLDL, nm 56.3 51.2−8.1 55.9 53.2 −5.0 56.5 55.9 −0.6 −7.7 −4.8 (IQR) (8.3) (8.4) (13.7)(8.7) (9.2) (14.1) (10.0) (11.3) (14.3) <0.0001 <0.0001 LDL*, nm 19.820.0 +0.5 19.8 20.0 +0.5 19.8 19.9 0.0 +0.5 +0.5 (IQR) (0.5) (0.6) (2.5)(0.5) (0.6) (2.5) (0.6) (0.5) (2.5) 0.0031 0.0007 HDL, nm 8.7 8.6 −1.18.6 8.6 0.0 8.7 8.7 0.0 −1.2 0.0 (IQR) (0.3) (0.2) (3.5) (0.5) (0.5)(2.4) (0.3) (0.4) (3.5) 0.0014 0.4171 *Patient numbers (n) for LDL dataonly were 215, 221, and 211 for IPE 4 g/day, IPE 2 g/day and placebo,respectively.

These data show that 4 g/day of ethyl eicosapentaenoate significantlyreduced median VLDL and HDL particle sizes, with a modest butsignificant increase in LDL particle size compared to placebo.

As shown in Table 4 below, administration of 4 g per day of ethyleicosapentaenoate (e.g., in a composition according to the presentdisclosure) significantly reduced median percent changes from baselinecompared to placebo for both the FADI-16 ratio and the FADI-18 ratio.

TABLE 4 Placebo-Adjusted Effects of 4 g/day Ethyl Eicosapentaenoate onFADI Ratios. Plasma RBCs Parameter Definition % Change P % Change PFADI-16 Palmitoleic −6.8% <0.01 −15.7% <0.0001 acid/Palmitic acid(C16:1/C16:0) FADI-18 Oleic acid/ −9.8% <0.001 −3.1% <0.01 Stearic Acid(C18:1/C18:0)

Corresponding FIG. 2 shows percent change in FADI parameters compared toplacebo in both plasma (FIG. 2A) and in red blood cells (FIG. 2B). Dataare placebo-adjusted least square means values.

Endpoint data for subjects who were randomized and took at least onedose of any study drug, had baseline laboratory efficacy measurement,and had at least one valid post-randomization laboratory efficacymeasurement of any type is summarized below.

Endpoint data for a subset of the study population (a modifiedintent-to-treat group referred to herein as the “MITT” group) were alsoanalyzed. The MITT group included 687 individuals, each of which took atleast one dose of study drug, had a baseline laboratory efficacymeasurement, and had at least one post-randomization laboratory efficacymeasurement.

The baseline characteristics of the MITT subgroup were similar to thoseof the ITT population. The majority of subjects in the MITT populationdid not have coronary heart disease. A summary of the MITT subjects'diabetes and cardiovascular disease is shown in Table 5 below:

TABLE 5 Summary of diabetes and cardiovascular disease-MITT. Placebo 2g/day 4 g/day Total n, total 227 234 226 687 History of diabetes andCVD* 52 (22.9%) 49 (20.9%) 42 (18.6%) 143 (20.8%) History of diabetes;no CVD 113 (49.8%) 122 (52.1%) 123 (54.4%) 358 (52.1%) No history ofdiabetes 62 (27.3%) 63 (26.9%) 61 (27.0%) 186 (27.1%) *CVD defined ashistory of any of the following: MI, unstable angina, stable angina,angioplasty, bypass surgery, clinically significant myocardial ischemia,peripheral arterial disease, abdominal aortic aneurysm, TIA, stroke ofcarotid origin, or obstruction of carotid artery (>50%).

A summary of selected concomitant medications is shown in Table 6.

TABLE 6 Selected Concomitant medications-MITT. Placebo AMR101 2 g/dAMR101 4 g/d N = 233 N = 236 N = 233 n (%) n (%) n (%) HMG-CoA reductase233 (100.0) 236 (100.0) 232 (99.6) inhibitors Anti-hypertensive 190(81.5) 200 (84.7) 199 (85.4) agents Anti-platelet agent 141 (60.5) 135(57.2) 138 (59.2) (excluding heparin) Aspirin 135 (57.9) 130 (55.1) 133(57.1) Clopidogrel 26 (11.2) 20 (8.5) 18 (7.7) Asasantin 2 (0.9) 0 1(0.4) Cilostazol 1 (0.4) 0 0 Anti-diabetic agents 139 (59.7) 138 (58.5)141 (60.5) Concomitant medications were defined as those used during thedouble-blind treatment period. 1. In addition, 41 patients were on anHMG-CoA reductase inhibitor in combination with another medication. 2.Patient 0.57-061 (in the AMR101 4 g group) was not on a statin atrandomization and did not inform site personnel until Visit 5 (Week 4)that he had stopped taking his statin 1 week prior to randomization.Patient 057-061 continued in the study; however, because the patient wasnot on a statin at the time baseline lipid measurements were drawn atVisit 4 (Week 0), the statin was not restarted following Visit 5.

A summary of statin use by MITT subjects (by intensity of therapy atrandomization) is shown in Table 7.

TABLE 7 Statin use at randomization (by intensity)-MITT. Placebo AMR1012 g/d AMR101 4 g/d N = 227 N = 234 N = 226 n (%) n (%) n (%) Lowerintensity 14 (6.2) 15 (6.4) 16 (7.1) Simvastatin 5 mg 4 (1.8) 4 (1.7) 2(0.9) Simvastatin 5 mg + 0 1 (0.4) 0 eze* Simvastatin 10 mg 10 (4.4) 10(4.3) 13 (5.8) Simvastatin 15 mg 0 0 1 (0.4) Medium intensity 140 (61.7)147 (62.8) 141 (62.4) Atorvastatin 10 mg 10 (4.4) 8 (3.4) 9 (4.0)Atorvastatin 20 mg 14 (6.2) 18 (7.7) 15 (6.6) Rosuvastatin 5 mg 9 (4.0)7 (3.0) 8 (3.5) Rosuvastatin 5 mg + 1 (0.4) 0 0 eze Rosuvastatin 10 mg21 (9.3) 28 (12.0) 19 (8.4) Rosuvastatin 10 mg + 1 (0.4) 0 1 (0.4) ezeSimvastatin 10 mg + 0 3 (1.3) 1 (0.4) eze Simvastatin 20 mg 31 (13.7) 32(13.7) 31 (13.7) Simvastatin 20 mg + 5 (2.2) 3 (1.3) 4 (1.8) ezeSimvastatin 40 mg 47 (20.7) 48 (20.5) 53 (23.5) Simvastatin 60 mg 1(0.4) 0 0 Higher intensity 73 (32.2) 72 (30.8) 69 (30.5) Atorvastatin 40mg 16 (7.0) 9 (3.8) 12 (5.3) Atorvastatin 40 mg + 1 (0.4) 2 (0.9) 0 ezeAtorvastatin 60 mg 0 1 (0.4) 0 Atorvastatin 80 mg 4 (1.8) 4 (1.7) 4(1.8) Atorvastatin 80 mg + 0 1 (0.4) 1 (0.4) eze Rosuvastatin 20 mg 20(8.8) 15 (6.4) 21 (9.3) Rosuvastatin 20 mg + 0 2 (0.9) 0 ezeRosuvastatin 40 mg 2 (0.9) 3 (1.3) 5 (2.2) Rosuvastatin 40 mg + 0 2(0.9) 0 eze Simvastatin 40 mg + 10 (4.4) 10 (4.3) 6 (2.7) ezeSimvastatin 80 mg + 0 4 (1.7) 2 (0.9) eze *Note: Ezetimibe includespatients on 5 mg or 10 mg

A summary of subjects' statin use before and during the study is shownin Table 8.

TABLE 8 Statin use-MITT. Category Placebo AMR101 2 g/d AMR101 4 g/dTotal N = 227 N = 234 N = 226 N = 687 n (%) n (%) n (%) n (%) Patientstaking a statin prior 203 (89.4) 212 (90.6) 205 (90.7) 620 (90.2) toscreening Continued statin after screening 190 (83.7) 198 (84.6) 194(85.8) 582 (84.7) Continued dose 187 (82.4) 194 (82.9) 190 (84.1) 571(83.1) Changed dose 3 (1.3) 4 (1.7) 4 (1.8) 11 (1.6) Changed statinafter screening 13 (5.7) 14 (6.0) 11 (4.9) 38 (5.5) Patients not takinga statin 24 (10.6) 22 (9.4) 21 (9.3) 67 (9.8) prior to screening

As shown in Table 9 below, subjects in the MITT group receiving 4 g/dayof study drug experienced a 17.5% median reduction in triglyceridescompared to baseline, while MITT subjects receiving 2 g/day of studydrug reduced median triglycerides by 2.6% compared to baseline. Placebosubjects' median triglycerides increased by 5.9% over baseline.

TABLE 9 Change in Fasting Triglycerides from Baseline to Week 12-MITT.Baseline[2] Week 12 EP Percent change from Baseline Difference fromplacebo Treatment + n Median [3] Median Median Estimated Statin [1](IQR) (IQR) (IQR) (Q1, Q3) p-value median 95% CI p-value Placebo 227259.0 (81.0) 269.5 (149.5) 5.9 (44.9) (−13.5, 31.3) 0.0002 — — — AMR101234 254.0 (92.5) 244.3 (117.0) −5.6 (34.5)  (−21.1, 13.4) 0.1111 −10.1(−15.7, −4.5)  0.0005 2 g/d AMR101 226 264.8 (93.0) 220.8 (92.0)  −17.5(31.0)  (−30.5, 0.5)  <0.0001 −21.5 (−26.7, −16.2) <0.0001 4 g/d [1]Only patients with non-missing baseline and Week 12 endpoint values wereincluded. [2]Baseline was defined as the average of Visit 4 (Week 0) andthe preceding lipid qualifying visit (either Visit 3 [Week −1] or if itoccurred, Visit 3.1) measurements. If the measurement at 1 visit wasmissing, the other visit was used. If the measurements at both visitswere missing, the last valid measurement prior to dosing with study drugwas used as the baseline value. [3] The Week 12 endpoint was defined asthe average of Visit 6 (Week 11) and Visit 7 (Week 12) measurements. Ifthe measurement at 1 visit was missing, the other visit was used. If themeasurements at both visits were missing, the last valid post-baselinemeasurement during the double-blind treatment period was used as theendpoint measurement. CI = confidence interval; EP = endpoint; IQR =interquartile range; Q1 = first quartile; Q3 = third quartile

Data for individual MITT subjects corresponding to Table 9 is shown in abox-and-whisker plot in FIG. 3.

Table 10 shows the percentage of subjects achieving triglyceridetreatment goal (less than 150 mg/dL) at Week 12.

TABLE 10 Percentage of Subjects Achieving Triglyceride Goal at Week 12.Placebo 2 g/day 4 g/day Total n 227 234 226 Achieved TG Goal 13 9 16Percentage Achieving 5.7% 3.8% 7.1% TG Goal

Table 11 shows changes in lipid parameters by statin type in the MITTgroup.

TABLE 11 Changes in Lipid Parameters by Statin Type-MITT. Pbo + statinAMR 101 2 g + statin Median Median BL [2] EOT [3] % chg % chg n MedianMedian from p from n BL EOT from p from Parameter Statin [1] (IQR) (IQRBL BL [1] [2] [3] BL BL TG Atorva 45 247 266.0 7.8 0.1729 43 235.0 245.0−0.5 0.5764 (71.0) (142.5) (89.0) (125.0) Simva 128 262.0 274.5 6.00.0016 134 256.5 241.3 −8.8 0.0176 (97.8) (148.3) (102.0) (133.0) Rosuva54 258.8 268.3 −0.6 0.1437 57 258.0 252.5 −5.8 0.9656 (69.0) (147.0)(93.5) (99.0) LDL-C Atorva 45 85.0 88.0 6.8 0.1239 43 82.0 88.0 4.90.0264 (24.0) (32.0) (21.0) (29.0) Simva 127 83.0 88.0 8.6 0.0003 13385.0 88.0 1.8 0.0954 (30.0) (31.0) (25.0) (25.0) Rosuva 54 81.0 89.510.5 0.0016 57 78.0 87.0 4.3 0.0365 (28.0) (30.0) (25.) (34.0) Non-HDL-CAtorva 45 132.0 141.0 4.2 0.0139 42 128.0 135.0 10.5 <0.0001 (30.0)(39.0) (37.0) (46.0) Simva 128 128.0 135.0 9.2 <0.0001 134 128.0 133.50.0 0.0862 (37.5) (45.0) (34.0) (41.0) Rosuva 54 126.0 145 12.8 <0.000157 125.0 133.0 2.7 0.0659 (25.0) (40.0) (30.0) (44.0) AMR 101 2 g +statin AMR 101 4 g + statin p Median Diff value % chg Diff p value fromfrom n BL EOT from p from from from Parameter Statin pbo pbo[4] [1] [2][3] BL BL pbo pbo [4] TG Atorva −2.4 0.6642 41 281.5 216.0 −23.9 <0.0001−28.4 <0.0001 (59.0) (82.5) Simva −14.3 0.0004 131 262.0 228.0 −14.7<0.0001 −18.8 <0.001 (106.0) (114.5) Rosuva −5.7 0.2512 54 250.8 204.0−20.5 0.0001 −23.4 <0.0001 (85.5) (77.0) LDL-C Atorva 1.1 0.8477 40 78.582.5 9.0 0.0358 2.5 0.6188 (24.5) (29.5) Simva −4.8 0.0844 131 82.0 83.01.5 0.2468 −5.4 0.0539 (24.0) (27.0) Rosuva −4.2 0.3482 54 85.0 82.5−3.8 0.3532 −14.8 0.0033 (33.0) (40.0) Non-HDL-C Atorva 2.0 0.7259 41131.0 122.0 −6.3 0.0936 −13.5 0.0071 (30.0) (32.0) Simva −6.8 0.0067 131128.0 125.0 −4.3 0.3514 −11.1 <0.0001 (35.0) (38.0) Rosuva −9.0 0.048154 128.5 118.0 −5.5 0.0240 −20.0 <0.0001 (28.0) (42.0) The mediandifferences between the treatment groups were estimated with theHodges-Lehmann method. [1] Only patients with both baseline and Week 12endpoint values are included. [2] Baseline for TG was defined as theaverage of the measurements at Visit 4 (Week 0) and the preceding lipidqualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1)measurements. If the measurement at 1 visit was missing, the other visitmeasurement was used. If the measurements at both visits were missing,the last valid measurement prior to dosing with study drug was used asthe baseline value. Baseline for other parameters were defined as theVisit 4 (Week 0) measurement. If missing, the last valid measurementprior to dosing with study drug was used. [3] For TG: the Week 12endpoint was defined as the average of measurements at Visit 6 (Week 11)and Visit 7 (Week 12). If the measurement at 1 visit was missing, theother visit measurement was used. If the measurements at both visitswere missing, the last valid post-baseline measurement during thedouble-blind treatment period was used as the endpoint measurement. Forother lipid parameters, the Week 12 endpoint was defined as the Visit 7(Week 12) measurement. If missing, the LOCF method was used. [4]P-valueis from the Wilcoxon rank-sum test. BL = Baseline; pbo = placebo; EOT =end of treatment (Week 12 endpoint); IQR = interquartile range; LOCF =last observation carried forward; Q1 = first quartile; Q3 = thirdquartile.

Table 12 shows changes in lipid parameters by statin regimen intensityin the MITT group.

TABLE 12 Changes in Lipid Parameters by Statin Regimen Intensity-MITT.Pbo + statin AMR 101 2 g + statin Median Median BL [2] EOT [3] % chg %chg Statin n Median Median from p from n BL EOT from p from ParameterPotency [1] (IQR) (IQR BL BL [1] [2] [3] BL BL TG Low 14 315.0 304.519.4 0.9515 15 256.0 208.5 −18.8 0.6387 (148.5) (158.5) (64.0) (162.0)Medium 140 257.3 268.3 4.6 0.0047 148 253.8 248.0 −5.3 0.3500 (83.5)(131.3) (83.0 (116.0) High 73 257.5 266.0 6.5 0.0210 71 256.5 239.5 −5.80.2668 (76.5) (160.0) (103.5) (115.0) LDL-C Low 14 101.5 98.0 −4.40.2661 15 91.0 95.0 0.9 0.6788 (35.0) (41.0) (30.0) (20.0) Medium 14083.0 91.5 9.9 <0.0001 147 82.0 85.0 2.4 0.0168 (26.0) (34.0) (23.0)(25.0) High 72 83.0 84.0 8.3 0.0133 71 83.0 91.0 3.1 0.0205 (27.0)(26.0) (26.0) (35.0) Non-HDL-C Low 14 150 152 1.5 0.7609 15 139 135 −2.20.5614 (50.0) (45.0) (20.0) (28.0) Medium 140 128 140 10.5 <0.0001 148127 133 1.7 0.0094 (35.0) (43.0) (36.0) (40.0) High 73 126 134 12.3<0.0001 71 128 142 5.4 0.0030 (27.0) (41.0) (31.0) (47.0) AMR 101 4 g +statin AMR 101 2 g + statin Median Diff p value % chg Diff p valueStatin from from n BL EOT from p from from from Parameter Potency pbopbo[4] [1] [2] [3] BL BL pbo pbo [4] TG Low −13.8 0.6784 16 267.8 256.80.5 0.6387 −13.1 0.5467 (87.0) (131.5) Medium −8.7 0.0139 141 269.0221.0 −15.8 <0.0001 −20.1 <0.0001 (96.5) (91.0) High −11.7 0.0200 69254.5 214.5 −20.2 <0.0001 −26.0 <0.0001 (92.5) (87.0) LDL-C Low 7.10.4450 16 78.5 84.5 7.8 0.0934 12.4 0.0483 (14.5) (20.0) Medium −5.90.0231 140 85.0 84.0 −2.2 0.9545 −10.0 0.0006 (28.0) (35.0) High −1.70.6410 69 79.0 82.0 5.4 0.1139 −2.9 0.4910 (22.0) (29.0) Non-HDL-C Low3.3 0.7107 16 128 131 −1.4 0.5282 2.4 0.6326 (24.0) (37.0) Medium −7.10.0031 141 129 124 −4.3 0.0618 −13.9 <0.0001 (35.0) (40.0) High −3.50.3266 69 128 118 −6.3 0.0212 −15.8 <0.0001 (31.0) (38.0) The mediandifferences between the treatment groups were estimated with theHodges-Lehmann method. Low intensity was defined as simvastatin 5-10 mg;medium intensity was defined as rosuvastatin 5-10 mg, atorvastatin 10-20mg, simvastatin 20-40 mg, or simvastatin 10-20 mg + ezetimibe 5-10 mg;High intensity was defined as rosuvastatin 20-40 mg, atorvastatin 40-80mg, simvastatin 80 mg, or simvastatin 40-80 mg + ezetimibe 5-10 mg. [1]Only patients with both baseline and Week 12 endpoint values areincluded. [2] Baseline for TG was defined as the average of themeasurements at Visit 4 (Week 0) and the preceding lipid qualifyingvisit (either Visit 3 [Week−1] or if it occurred, Visit 3.1)measurements. If the measurement at 1 visit was missing, the other visitmeasurement was used. If the measurements at both visits were missing,the last valid measurement prior to dosing with study drug was used asthe baseline value. Baseline for other parameters were defined as theVisit 4 (Week 0) measurement. If missing, the last valid measurementprior to dosing with study drug was used. [3] For TG: the Week 12endpoint was defined as the average of measurements at Visit 6 (Week 11)and Visit 7 (Week 12). If the measurement at 1 visit was missing, theother visit measurement was used. If the measurements at both visitswere missing, the last valid post-baseline measurement during thedouble-blind treatment period was used as the endpoint measurement. Forother lipid parameters, the Week 12 endpoint was defined as the Visit 7(Week 12) measurement. If missing, the LOCF method was used. [4]P-valueis from the Wilcoxon rank-sum test. BL = Baseline; pbo = placebo; EOT =end of treatment (Week 12 endpoint); IQR = interquartile range; LOCF =last observation carried forward; Q1 = first quartile; Q3 = thirdquartile.

Table 13 shows changes in lipid parameters by TG tertile in the MITTgroup.

TABLE 13 Changes in Lipid Parameters by TG Tertile-MITT. Pbo + statinAMR 101 2 g + statin Median Median Baseline BL [2] EOT [3] % chg % chgTG n Median Median from p from n BL EOT BL from p from Parameter tertile[1] (IQR) (IQR BL BL [1] [2] [3] BL BL TG Lowest 72 203.8 214.5 7.90.0055 84 205.8 207.8 0.7 0.1560 (31.5) (71.5) (33.0) (74.5) Middle 80257.8 263.5 3.3 0.3629 76 257.0 228.3 −13.0 0.0092 (30.3) (112.3) (30.5)(83.5) Highest 75 340.5 380.5 5.2 0.0039 74 348.5 320.3 −8.7 0.0914(94.0) (165.5) (75.0) (119.0) LDL-C Lowest 72 85.5 95.0 9.2 0.0002 8484.5 92.0 3.1 0.0656 (23.5) (28.0) (28.0) (32.0) Middle 80 86.5 90.0 7.30.0012 76 82.0 86.5 3.1 0.0161 (27.0) (26.5) (25.0) (23.5) Highest 7480.0 80.0 9.2 0.0821 73 81.0 85.0 1.7 0.1876 (33.0) (37.0) (24.0) (26.0)Non-HDL-C Lowest 72 117 134 12.1 <0.0001 84 121 129 6.9 0.0001 (23.0)(32.0) (32.0) (38.0) Middle 80 132 138 6.0 0.0004 76 129 132 −1.2 0.7214(26.0) (36.0) (30.0) (35.0) Highest 75 140 149 12.2 <0.0001 74 140 1503.0 0.0183 (48.0) (60.0) (44.0) (51.0) AMR 101 2 g + statin AMR 101 4g + statin p Median Baseline Diff value % chg Diff p value TG from fromn BL EOT from p from from from Parameter tertile pbo pbo[4] [1] [2] [3]BL BL pbo pbo [4] TG Lowest −4.1 0.3694 68 207.8 183.5 −10.9 0.1127−14.4 0.0020 (28.0) (67.5) Middle −9.9 0.0324 81 261.5 205.0 −19.3<0.0001 −17.9 <0.0001 (26.0) (74.5) Highest −16.9 0.0043 77 346.5 260.0−21.8 <0.0001 −31.1 <0.0001 (75.5) (110.5) LDL-C Lowest −5.7 0.0889 6882.5 83.0 −3.9 0.3336 −12.2 0.0007 (25.0) (30.5) Middle −2.6 0.4097 8081.5 82.5 2.1 0.3260 −5.8 0.1345 (29.5) (34.0) Highest −2.0 0.6672 7782.0 83.0 4.8 0.0289 0 0.9970 (25.0) (24.0) Non-HDL-C Lowest −4.2 0.192668 116 118 −2.0 0.4390 −13.8 <0.0001 (26.0) (31.0) Middle −7.0 0.0169 81127 124 −4.0 0.5345 −9.5 0.0039 (31.0) (42.0) Highest −5.0 0.2151 77 142130 −6.9 0.0030 −17.6 <0.0001 (36.0) (48.0) The median differencesbetween the treatment groups were estimated with the Hodges-Lehmannmethod. Baseline TG tertiles were <230.5 mg/dL, 230.5 to <289.5 mg/dL,and ≥289.5 mg/dL. [1] Only patients with both baseline and Week 12endpoint values are included. [2] Baseline for TG was defined as theaverage of the measurements at Visit 4 (Week 0) and the preceding lipidqualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1)measurements. If the measurement at 1 visit was missing, the other visitmeasurement was used. If the measurements at both visits were missing,the last valid measurement prior to dosing with study drug was used asthe baseline value. Baseline for other parameters were defined as theVisit 4 (Week 0) measurement. If missing, the last valid measurementprior to dosing with study drug was used. [3] For TG: the Week 12endpoint was defined as the average of measurements at Visit 6 (Week 11)and Visit 7 (Week 12). If the measurement at 1 visit was missing, theother visit measurement was used. If the measurements at both visitswere missing, the last valid post-baseline measurement during thedouble-blind treatment period was used as the endpoint measurement. Forother lipid parameters, the Week 12 endpoint was defined as the Visit 7(Week 12) measurement. If missing, the LOCF method was used. [4]P-valueis from the Wilcoxon rank-sum test. BL = Baseline; pbo = placebo; EOT =end of treatment (Week 12 endpoint); IQR = interquartile range; LOCF =last observation carried forward; Q1 = first quartile; Q3 = thirdquartile.

Table 14 shows changes in lipid parameters by non-statin washout statusin the MITT group.

TABLE 14 Changes in Lipid Parameters by Non-Statin Washout Status-MITT.Pbo + statin AMR 101 2 g + statin Non- Median Median statin BL [2] EOT[3] % chg % chg washout n Median Median from p from n BL EOT from p fromParameter (Yes/No) [1] (IQR) (IQR BL BL [1] [2] [3] BL BL TG Yes 100258.3 267.5 3.9 0.0075 109 262.5 249.5 −4.2 0.4771 (mg/dL) (81.8)(175.5) (95.5) (120.5) No 127 259.0 272.0 6.2 0.0105 125 247.5 229.0−7.9 0.1416 (85.5) (131.5) (87.0) (114.5) LDL-C Yes 100 82.0 84.5 9.50.0002 109 82.0 85.0 2.2 0.1289 (mg/dL) (27.5) (27.5) (24.0) (23.0) No126 85.0 90.0 7.3 0.0007 124 84.0 91.5 3.5 0.0024 (25.0) (35.0) (26.0)(32.5) Non-HDL-C Yes 100 124 136 10.7 <0.0001 109 127 133 0.0 0.0239(mg/dL) (31.0) (40.0) (30.0) (38.0) No 127 129 140 9.6 <0.0001 125 129135 3.8 0.0020 (35.0) (44.0) (35.0) (44.0) AMR 101 4 g + statin Non- AMR101 2 g + statin Median statin Diff p value % chg Diff p value washoutfrom from n BL EOT from p from from from Parameter (Yes/No) pbo pbo[4][1] [2] [3] BL BL pbo pbo [4] TG Yes −9.5 0.0292 92 269.3 220.8 −17.7<0.0001 −22.4 <0.0001 (mg/dL) (92.8) (80.8) No −10.7 0.0060 134 263.0220.0 −16.7 <0.0001 −20.8 <0.0001 (90.5) (100.0) LDL-C Yes −6.3 0.042391 82.0 80.0 −1.4 0.4932 −7.5 0.0428 (mg/dL) (28.0) (33.0) No −1.20.6549 134 82.0 83.5 2.5 0.2283 −5.1 0.0692 (25.0) (30.0) Non-HDL-C Yes−6.9 0.0345 92 129 124 −5.4 0.0900 −14.4 <0.0001 (mg/dL) (35.0) (36.0)No −4.6 0.0847 134 128 122 −4.9 0.0522 −4.8 <0.0001 (32.0) (42.0) Themedian differences between the treatment groups were estimated with theHodges-Lehmann method. [1] Only patients with both baseline and Week 12endpoint values are included. [2] Baseline for TG was defined as theaverage of the measurements at Visit 4 (Week 0) and the preceding lipidqualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1)measurements. If the measurement at 1 visit was missing, the other visitmeasurement was used. If the measurements at both visits were missing,the last valid measurement prior to dosing with study drug was used asthe baseline value. Baseline for other parameters were defined as theVisit 4 (Week 0) measurement. If missing, the last valid measurementprior to dosing with study drug was used. [3] For TG: the Week 12endpoint was defined as the average of measurements at Visit 6 (Week 11)and Visit 7 (Week 12). If the measurement at 1 visit was missing, theother visit measurement was used. If the measurements at both visitswere missing, the last valid post-baseline measurement during thedouble-blind treatment period was used as the endpoint measurement. Forother lipid parameters, the Week 12 endpoint was defined as the Visit 7(Week 12) measurement. If missing, the LOCF method was used. [4]P-valueis from the Wilcoxon rank-sum test. BL = Baseline; pbo = placebo; EOT =end of treatment (Week 12 endpoint); IQR = interquartile range; LOCF =last observation carried forward; Q1 = first quartile; Q3 = thirdquartile.

Table 15 shows changes in lipid parameters by diabetes status in theMITT group.

TABLE 15 Changes in Lipid Parameters by Diabetes Status-MITT. Pbo +statin AMR 101 2 g + statin Median Median BL [2] EOT [3] % chg % chgDiabetes n Median Median from p from n BL EOT from p from Parameter(Yes/No) [1] (IQR) (IQR) BL BL [1] [2] [3] BL BL TG Yes 165 259.0 275.56.2 0.0002 171 253.5 244.0 −1.5 0.7846 (mg/dL) (78.0) (153.5) (87.0)(116.5) No 62 258.8 258.5 4.3 0.3134 63 256.5 245.0 −12.1 0.0075 (123.5)(138.0) (96.0) (121.5) LDL-C Yes 164 84.0 87.5 8.8 <0.0001 170 82.0 87.02.2 0.0063 (mg/dL) (25.5) (31.0) (24.0) (26.0) No 62 85.5 90.0 8.50.0060 63 83.0 88.0 2.6 0.0674 (33.0) (31.0) (29.0) (35.0) Non-HDL-C Yes165 128 136 10.7 <0.0001 171 125 135 5.1 <0.0001 (mg/dL) (34.0) (44.0)(33.0) (41.0) No 62 129 143 8.3 0.0001 63 135 133 −0.7 0.7421 (33.0)(36.0) (31.0) (42.0) AMR 101 4 g + statin AMR 101 2 g + statin MedianDiff p value % chg Diff p value Diabetes from from n BL EOT from p fromfrom from Parameter (Yes/No) pbo pbo[4] [1] [2] [3] BL BL pbo pbo [4] TGYes −9.8 0.0074 165 262.0 216.5 −18.7 <0.0001 −23.2 <0.0001 (mg/dL)(92.0) (88.0) No −10.8 0.0261 61 271.5 234.5 −15.0 <0.0001 −16.8 0.0005(114.5) (90.0) LDL-C Yes −3.8 0.1482 165 81.0 83.0 2.0 0.2403 −6.30.0227 (mg/dL) (26.0) (29.0) No −3.1 0.3161 60 83.0 83.5 1.4 0.4317 −5.30.1402 (23.0) (37.0) Non-HDL-C Yes −4.4 0.0723 165 128 121 −5.5 0.0317−14.4 <0.0001 (mg/dL) (35.0) (40.0) No −8.6 0.0108 61 131 126 −0.90.3032 −11.3 0.0003 (38.0) (38.0) The median differences between thetreatment groups were estimated with the Hodges-Lehmann method. [1] Onlypatients with both baseline and Week 12 endpoint values are included.[2] Baseline for TG was defined as the average of the measurements atVisit 4 (Week 0) and the preceding lipid qualifying visit (either Visit3 [Week−1] or if it occurred, Visit 3.1) measurements. If themeasurement at 1 visit was missing, the other visit measurement wasused. If the measurements at both visits were missing, the last validmeasurement prior to dosing with study drug was used as the baselinevalue. Baseline for other parameters were defined as the Visit 4 (Week0) measurement. If missing, the last valid measurement prior to dosingwith study drug was used. [3] For TG: the Week 12 endpoint was definedas the average of measurements at Visit 6 (Week 11) and Visit 7 (Week12). If the measurement at 1 visit was missing, the other visitmeasurement was used. If the measurements at both visits were missing,the last valid post-baseline measurement during the double-blindtreatment period was used as the endpoint measurement. For other lipidparameters, the Week 12 endpoint was defined as the Visit 7 (Week 12)measurement. If missing, the LOCF method was used. [4]P-value is fromthe Wilcoxon rank-sum test. BL = Baseline; pbo = placebo; EOT = end oftreatment (Week 12 endpoint); IQR = interquartile range; LOCF = lastobservation carried forward; Q1 = first quartile; Q3 = third quartile.

Table 16 shows lipid changes in placebo-treated subjects in variousclinical trials in the MITT group.

TABLE 16 Lipid changes in placebo-treated subjects in various clinicaltrials-MITT. Background Central Study/Active statin Lead-in tendencyDuration drug Population Placebo therapy period measure of PBO n Veryhigh TG population (≥500 mg/dL) MARINE TG 500-2000 Mineral 25% on 4 to 6Median % 12 wks 75 Icosapent Ethyl¹ mg/dL oil statin wks CFB HarrisPownall TG 500-2000 Corn oil No 6 wks Median % 6-16 42 pooled analysis/mg/dL CFB wks Omega 3 acid Ethyl Esters²,³ Goldberg⁴/ TG 500-1500 Yes No6 to 12 Mean %  8 wks 44 Fenofibrate mg/dL weeks CFB High TG population(200-500 mg/dL) ANCHOR TG 200-499 Mineral Simva 6 to 8 wks Median % 12wks 227 Icosapent mg/dL oil Atorva Stopped all CFB Ethyl⁵ Rosuva +/−lipid meds Eze except statin COMBOS/ TG 200-499 Corn oil Simva 40 8 wksstopped Median %  8 wks 132 Omega 3 Ethyl mg/dL mg all lipid meds CFBEsters⁶ start simva 40 Goldberg⁷/ TG 350-499 Yes No 6 to 12 Mean %  8wks 28 mg/dL weeks CFB Simvastatin⁸ Type IV LDL- Yes No 4 weeks Median % 6 weeks 74 C < 160 CFB TG > 200 Atorvastatin⁹ Type IV Yes No Yesduration Median % NR 12 not specified CFB Rosuvastatin¹⁰ Primary htg YesNo 6 week Median %  6 wks 26 CFB Niacin ER¹¹ Primary Yes No Not Mean %16 wks 73 hyperlipidemia specified CFB and mixed dyslipidemia FIRST/Mixed Yes Atorva up to 2 to 10 Mean % 24 mos 329 Fenofibric dyslipidemia40 mg weeks CFB acid¹² TG ≥ 150 HDL-C ≤ 45 M or ≤ 55 FLDL-C ≤ 100Study/Active drug TG LDLc nHDLc TC HDLc VLDLc apo B Very high TGpopulation (≥500 mg/dL) MARINE +9.7 −3.0 +7.8 +7.7  0.0 +13.7 +4.3Icosapent Ethyl¹ Harris Pownall +6.7 −4.8 −3.6 −1.7  0.0 −0.9 NR pooledanalysis/ Omega 3 acid Ethyl Esters²,³ Goldberg⁴/ +7.2 −4.2 NR +0.4 +5.0+11.0 NR Fenofibrate High TG population (200-500 mg/dL) ANCHOR +5.9 +8.8+9.8 +9.1 +4.8 +15.0 +7.1 Icosapent Ethyl⁵ COMBOS/ −6.3 −2.8 −2.2 −1.7−1.2 −7.2 −1.9 Omega 3 Ethyl Esters⁶ Goldberg⁷/ −0.5 +12.0  NR +2.8 +4.0+5.8 NR Simvastatin⁸ −9   +1   +1 +2 +3   −7 NR Atorvastatin⁹ −12.4 +3.6 −2.8 −2.3 +3.8 −1.0 NR Rosuvastatin¹⁰ +0.8 +4.5 +1.7 +1.2 −2.9 +2.1−0.2 Niacin ER¹¹ +12   +1   NR +2 +2   NR +1   FIRST/ −2*  +2*  *0 NR+3*  NR NR Fenofibric Median acid¹² % CFB ¹Bays H E et al.Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with veryhigh triglyceride levels (from the Multi-center, placebo-controlled,Randomized, double-blind, 12-week study with an open-label ExtensionMARINE. Am J Cardiol. 2001; 108(5): 682-90. ²Pownall H J et al.Correlation of serum triglyceride and its reduction by omega-3 fattyacids with lipid transfer activity and the neutral lipid compositions ofhigh-density and low-density lipoproteins. Atherosclerosis 1999; 143:285-97. ³Harris W S et al. Safety and efficacy of Omacor in severehypertriglyceridemia. J Cardiovasc Risk 1997; 4(5-6): 385-91. ⁴GoldbergA C et al. Fenofibrate for the treatment of type IV and type Vhyperlipoproteinemias: a double-blind, placebo-controlled multicenter USstudy. Clin Ther. 1989; 11(1): 69-83. ⁵Ballantyne C M et al. Efficacyand safety of eicosapentaenoic acid ethyl ester (AMR101) therapy instatin-treated patients with persistent high triglycerides (from theANCHOR study). Amj Cardiol. 2012; 110(7): 984-92. ⁶Davidson M H et al.COMBination of prescription Omega-3 with Simvastatin (COMBOS)Investigators. Efficacy and tolerability of adding prescription omega-3fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemicpatients: an 8-week randomized, double-blind, placebo-controlled study.Clin Ther. 2007; 29(7); 1354-67. ⁷Goldberg A C et al. Fenofibrate forthe treatment of type IV and type V hyperlipoproteinemias: adouble-blind, placebo-controlled multicenter US study. Clin Ther. 1989;11(1): 69-83. ⁸Zocor (simvastatin) Prescribing Information, 2012. MerckSharp & Dohme Ltd. ⁹Lipitor (atorvastatin calcium) Prescribinginformation, 2013. Pfizer Inc. ¹⁰Crestor (rosuvastatin calcium)Prescribing information, 2013. AstraZeneca ¹¹NIASPAN (niacinextended-release) Prescribing information, 2013. AbbVie LTD. ¹²DavidsonM H et al. Results from the fenofibric acid on carotid intima-mediathickness in subjects with Type IIb dyslipidemia with residual risk inaddition to atorvastatin (FIRST) trial. J Am Col Cardiol. 2013;61(10-2): E1434. NR: not reported; % CFB: percent change from baseline;*Results at 13 week timepoint

Table 17 shows percent change from baseline and difference from placebofor secondary endpoints in the MITT group.

TABLE 17 Percent change from baseline and difference from placebo forsecondary endpoints-MITT. Percent change from Baseline Difference fromplacebo Treatment + n Baseline[2] Week 12 EP [3] Median EstimatedAdjusted Statin [1] Median (IQR) Median (IQR) (IQR) (Q1, Q3) p-valuemedian 95% CI p-value [4] LDL-C (mg/dL) Placebo 226 84.0 (27.0) 88.5(31.0) 8.8 (31.0) (−7.8, 23.2) <0.0001 — — — AMR101 2 g/d 234 82.0(24.0) 87.0 (27.0) 2.4 (26.1) (−8.3, 17.7) 0.0010 −3.6 (−7.9, 0.5)0.0867 AMR101 4 g/d 225 82.0 (25.0) 83.0 (31.0) 1.5 (26.6) (−11.6,15.0)  0.1733 −6.2 (−10.5, −1.7) 0.0067 Non-HDL-C (mg/dL) Placebo 227128.0 (34.0)  138.0 (43.0)  9.8 (27.6) (−3.5, 24.1) <0.0001 — — — AMR1012 g/d 234 128.0 (33.0)  134.0 (41.0)  2.4 (26.1) (−7.0, 19.0) 0.0001−5.5  (−9.4, −1.7) 0.0140 AMR101 4 g/d 226 128.0 (32.0)  122.0 (39.0) −5.0 (21.3)  (−13.5, 7.8)  0.0106 −13.6  (−17.2, −9.9) 0.0001 Apo B(mg/dL) Placebo 219 91.0 (24.0) 98.0 (25.0) 7.1 (23.2) (−4.7, 18.6)<0.0001 — — — AMR101 2 g/d 227 91.0 (22.0) 95.0 (24.0) 1.6 (20.7) (−6.4,14.3) 0.0001 −3.8  (−6.9, −0.7) 0.0170 AMR101 4 g/d 217 93.0 (23.0) 90.0(25.0) −2.2 (16.4)  (−10.2, 6.2)  0.0759 −9.3 (−12.3, −6.1) 0.0001VLDL-C (mg/dL) Placebo 226 42.0 (21.0) 49.0 (28.0) 15.0 (58.8)  (−10.9,47.8)  <0.0001 — — — AMR101 2 g/d 233 43.0 (21.0) 44.0 (25.0) 1.6 (54.6)(−20.0, 34.5)  0.0287 −10.5  (−18.3, −2.5) 0.0170 AMR101 4 g/d 225 44.0(21.0) 38.0 (22.0) −12.1 (47.9)  (−31.3, 16.7)  0.0043 −24.4   (−31.9,−17.0) 0.0001 Lp-PLA2 (ng/mL) Placebo 213 185.0 (58.0)  200.0 (71.0) 6.7 (24.0) (−6.4, 17.6) <0.0001 — — — AMR101 2 g/d 224 190.0 (55.5) 183.5 (57.5)  −1.8 (23.1)  (−12.7, 10.4)  0.2686 −8.0 (−11.6, −4.5)0.0004 AMR101 4 g/d 217 180.0 (56.0)  160.0 (57.0)  −12.8 (18.5) (−22.1, −3.6)  <0.0001 −19.0   (−22.2, −15.7) 0.0001 [1] Only patientswith non-missing baseline and Week 12 endpoint values were included.[2]Baseline was defined as the Visit 4 (Week 0) measurement. If missing,the last valid measurement prior to dosing with study drug was used. [3]The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement.If missing, the LOCF method was used. [4] The adjusted p-value wasobtained from applying Hommel's multiple comparison procedure to thep-value from the treatment comparison between the AMR101 4 g or 2 g withplacebo with exception of LDL-C CI = confidence interval; EP = endpoint;IQR = interquartile range; Q1 = first quartile; Q3 = third quartile

Table 18 shows percent change from baseline and difference from placebofor lipid exploratory endpoints in the MITT group.

TABLE 18 Percent Change from Baseline and Difference from Placebo forLipid Exploratory Endpoints-MITT Population. Percent change fromBaseline Difference from placebo Treatment + n Baseline[2] Week 12 EP[3] Median Estimated Statin [1] Median (IQR) Median (IQR) (IQR) (Q1, Q3)p-value median 95% CI p-value Total cholesterol (mg/dL) Placebo 227168.0 (38.0) 181.0 (46.0) 9.1 (20.8) (−1.4, 19.4) <0.0001 — — — AMR101 2g/d 234 169.0 (34.0) 175.0 (44.0) 2.1 (19.6) (−4.4, 15.2) <0.0001  −4.8 (−7.8, −1.8) 0.0019 AMR101 4 g/d 226 167.0 (38.0) 162.0 (38.0) −3.2(16.8)  (−11.3, 5.5)  0.0023 −12.0 (−14.9, −9.2) <0.0001  HDL-C (mg/dL)Placebo 227  39.0 (12.0)  40.0 (14.0) 4.8 (22.0) (−7.7, 14.3) <0.0001 —— — AMR101 2 g/d 234  38.0 (13.0)  38.0 (11.0)   0 (19.5) (−7.7, 11.8)0.0164  −2.2 (−4.9, 0.5) 0.1265 AMR101 4 g/d 226  37.0 (12.0)  37.0(13.0) −1.0 (18.2)  (−8.7, 9.5)  0.8474  −4.5  (−7.4, −1.8) 0.0013VLDL-TG (mg/dL) Placebo 226 183.0 (94.0)  196.0 (136.0) 8.9 (63.8)(−19.3, 44.5)  <0.0001 — — — AMR101 2 g/d 233 185.0 (86.0) 168.0 (98.0)−2.1 (48.9)  (−26.3, 22.6)  0.8897 −11.3 (−19.4, −3.4) 0.0049 AMR101 4g/d 225 190.0 (99.0) 147.0 (88.0) −19.2 (46.2)  (−39.2, 7.0)  <0.0001−26.5  (−33.9, −19.0) <0.0001  Apo A1 (mg/dL) Placebo 219 140.0 (35.0)145.0 (34.0) 3.6 (14.9) (−2.1, 12.1) <0.0001 — — — AMR101 2 g/d 227140.0 (26.0) 141.0 (26.0) 2.0 (13.0) (−4.0, 9.0)  0.0007  −1.7 (−3.7,0.3) 0.0943 AMR101 4 g/d 217 141.0 (31.0) 137.0 (29.0) −2.9 (12.6) (−9.6, 3.1)  <0.0001  −6.9  (−8.9, −4.9) <0.0001  Apo B/ApoA1 ratioPlacebo 219  0.7 (0.2)  0.7 (0.2) 2.4 (21.7) (−7.8, 13.9) 0.0028 — — —AMR101 2 g/d 227  0.7 (0.2)  0.7 (0.2) 0.1 (18.3) (−7.9, 10.4) 0.2523 −2.0 (−5.0, 0.9) 0.1886 AMR101 4 g/d 217  0.7 (0.2)  0.7 (0.2) −0.7(20.3)  (−8.1, 12.2) 0.4097  −2.4 (−5.4, 0.8) 0.1333 Lp(a) (mg/dL)Placebo 83  12.0 (31.0)  12.0 (37.0) 0.0 (35.0) (−8.3, 26.7) 0.0452 — —— AMR101 2 g/d 83  11.0 (33.0)  12.0 (33.0) 0.0 (24.9) (−2.5, 22.4)0.0011  0.0 (−2.5, 8.3) 0.5466 AMR101 4 g/d 81  7.0 (33.0)  9.0 (31.0)0.0 (10.0) (−6.5, 3.4)  0.4722  0.0 (−8.3, 0.0) 0.3626 RLP-C (mg/dL)Placebo 86 14.0 (7.0) 13.0 (9.0) 8.0 (66.9) (−29.4, 37.5)  0.1316 — — —AMR101 2 g/d 84 15.0 (7.0) 11.0 (7.0) −11.1 (40.0)  (−30.0, 10.0) 0.0124 −16.7 (−30.0, 10.0) 0.0153 AMR101 4 g/d 82 13.5 (6.0) 10.0 (6.0)−24.0 (45.5)  (−45.5, 0.0)  0.0002 −25.8  (−39.9, −12.4) 0.0001 OxidizedLDL (U/L) Placebo 84  51.8 (16.8)  59.7 (18.1) 11.6 (28.1)  (−4.0, 24.1)<0.0001 — — — AMR101 2 g/d 75  54.0 (17.8)  55.8 (22.8) 2.6 (18.3)(−4.5, 13.8) 0.0245  −5.8 (−11.9, 0.9)  0.0946 AMR101 4 g/d 78  54.0(14.6)  51.4 (17.5) −4.8 (19.6)  (−11.5, 8.1)  0.0610 −13.3 (−19.3,−7.5) <0.0001  [1] Only patients with non-missing baseline and Week 12endpoint values were included. [2]Baseline was defined as the Visit 4(Week 0) measurement. If missing, the last valid measurement prior todosing with study drug was used. [3] The Week 12 endpoint was defined asthe Visit 7 (Week 12) measurement. If missing, the LOCF method was used.CI = confidence interval; EP = endpoint; IQR = interquartile range; Q1 =first quartile; Q3 = third quartile

Table 19 shows change from baseline and difference from placebo for LDLParticle Concentration and Size in the MITT group.

TABLE 19 Change from Baseline and Difference from Placebo for LDLParticle Concentration and Size-MITT Population. Percent change fromBaseline Difference from placebo Treatment + n Baseline[2] Week 12 EP[3] Median Estimated Statin [1] Median (IQR) Median (IQR) (IQR) (Q1, Q3)p-value median 95% CI p-value LDL Particle Concentration (nmol/L)Placebo 211 1152.0 (353.0) 1287.0 (456.0) 11.9 (31.6)  (−3.0, 28.6)<0.0001 — — — AMR101 2 g/d 222 1170.5 (349.0) 1215.0 (355.0)  4.7 (29.2)(−10.3, 18.9) 0.0008 −7.5  (−12.1, −2.9) 0.0013 AMR101 4 g/d 216 1130.5(369.5) 1190.5 (512.0)  3.8 (31.8) (−11.0, 20.8) 0.0016 −7.7  (−12.3,−2.8) 0.0017 LDL Particle Size (nm) Placebo 211 19.8 (0.6) 19.9 (0.5)0.0 (2.5) (−1.0, 1.5) 0.3037 — — — AMR101 2 g/d 221 19.8 (0.5) 20.0(0.6) 0.5 (2.5) (−0.5, 2.0) <0.0001 0.5  (0.5, 1.0) 0.0007 AMR101 4 g/d215 19.8 (0.5) 20.0 (0.6) 0.5 (2.5) (−0.5, 2.0) <0.0001 0.5  (0.0, 1.0)0.0031 [1] Only patients with non-missing baseline and Week 12 endpointvalues were included. [2]Baseline was defined as the Visit 4 (Week 0)measurement. If missing, the last valid measurement prior to dosing withstudy drug was used. [3] The Week 12 endpoint was defined as the Visit 7(Week 12) measurement. If missing, the LOCF method was used. CI =confidence interval; EP = endpoint; IQR = interquartile range; Q1 =first quartile; Q3 = third quartile

Table 20 shows change from baseline and difference from placebo forglucose metabolism exploratory endpoints in the MITT group.

TABLE 20 Change from baseline and difference from placebo for glucosemetabolism exploratory endpoints-MITT. Mean Change from BaselineDifference from placebo Treatment + n Baseline[2] Week 12 EP [3] LS MeanLS Mean Statin [1] Mean (SD) Mean (SD) (SE) (95% CI) p-value (SE) 95% CIp-value Fasting plasma glucose (mg/dL) Placebo 219 128.9 (35.2)  133.7(38.5)   4.2 (2.1)  (0.0, 8.4) 0.0032 — — — AMR101 2 g/d 226 134.8(42.6)  138.0 (44.9)   3.6 (2.1) (−0.5, 7.7) 0.0042 −0.6 (3.0)  (−6.5,5.3) 0.8408 AMR101 4 g/d 217 133.1 (37.0)  141.9 (51.1)   8.9 (2.1) (4.7, 13.1) 0.0007 4.7 (3.0)  (−1.2, 10.6) 0.1200 HbA1c (%) Placebo 2186.5 (0.9) 6.7 (1.1)  0.2 (0.04)  (0.1, 0.2) <0.0001 — — — AMR101 2 g/d228 6.7 (1.1) 6.8 (1.2)  0.2 (0.04)  (0.1, 0.2) <0.0001 −0.0 (0.05)(−0.1, 0.1) 0.9392 AMR101 4 g/d 220 6.6 (0.9) 6.9 (1.1)  0.3 (0.04) (0.2, 0.3) <0.0001  0.1 (0.05) (−0.0, 0.3) 0.0899 Insulin (μIU/mL)Placebo 215 23.0 (33.1) 20.1 (17.5) −1.2 (0.9) (−2.9, 0.6) 0.1568 — — —AMR101 2 g/d 217 18.6 (11.5) 18.6 (11.0) −1.2 (0.9) (−3.0, 0.5) 0.5685−0.1 (1.3)  (−2.6, 2.4) 0.9567 AMR101 4 g/d 215 19.6 (16.0) 19.0 (16.2)−1.1 (0.9) (−2.9, 0.6) 0.9601 0.0 (1.3) (−2.5, 2.5) 0.9874 HOMA-IRPlacebo 215  8.1 (16.4) 6.9 (6.9) −0.4 (0.4) (−1.2, 0.3) 0.4806 — — —AMR101 2 g/d 217 6.4 (4.8) 6.4 (4.5) −0.6 (0.4) (−1.3, 0.2) 0.4192 −0.1(0.5)  (−1.2, 0.9) 0.8022 AMR101 4 g/d 213 6.8 (7.0) 6.9 (6.7) −0.1(0.4) (−0.8, 0.7) 0.2462 0.3 (0.6) (−0.7, 1.4) 0.5225 [1] Only patientswith non-missing baseline and Week 12 endpoint values were included.[2]Baseline was defined as the Visit 4 (Week 0) measurement. If missing,the last valid measurement prior to dosing with study drug was used. [3]The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement.If missing, the LOCF method was used. LS means, SE, CI, and p-values arefrom linear contrasts of an ANCOVA model of change from baseline to Week12 EP with treatment as a factor and baseline value as a covariate. CI =confidence interval; EP = endpoint; SE = standard error; SD = standarddeviation

Table 21 shows change from baseline and difference from placebo forinflammatory biomarkers in the MITT group.

TABLE 21 Change from Baseline and Difference from Placebo forInflammatory Biomarkers-MITT. Percent change from Baseline Differencefrom placebo Treatment + n Baseline[2] Week 12 EP [3] Median EstimatedStatin [1] Median (IQR) Median (IQR) (IQR) (Q1, Q3) p-value median 95%CI p-value ICAM-1 (ng/mL) Placebo 83 269.0 (122.0) 257.0 (131.0)  9.0(31.0)  (−6.0, 25.0) 0.0085 — — — AMR101 2 g/d 74 267.0 (97.0)  268.5(89.0)   1.5 (37.0) (−15.0, 22.0) 0.3718 −6.0 (−15.0, 3.0)  0.2086AMR101 4 g/d 78 273.0 (96.0)  270.0 (110.0)  2.5 (40.0) (−18.0, 22.0)0.4487 −6.0 (−16.0, 4.0)  0.1910 IL-6 (pg/mL) Placebo 83 3.2 (3.2) 2.9(3.0) 0.1 (1.8) (−0.8, 0.9) 0.6566 — — — AMR101 2 g/d 74 2.4 (2.0) 2.7(2.3) 0.2 (1.3) (−0.4, 0.9) 0.1344  0.1 (−0.3, 0.6) 0.5979 AMR101 4 g/d78 2.7 (2.6) 2.6 (2.1) 0.1 (1.8) (−1.0, 0.8) 0.9920 −0.1 (−0.6, 0.4)0.7608 PAI-1 (ng/mL) Placebo 54 72.2 (62.0) 86.4 (60.7) −1.7 (73.3)(−29.1, 44.2) 0.8618 — — — AMR101 2 g/d 50 28.1 (58.1) 90.3 (67.4) 14.6(38.8)  (−8.7, 30.1) 0.0551 12.1  (−9.1, 29.4) 0.2631 AMR101 4 g/d 5584.7 (73.5) 85.6 (86.3) −3.1 (45.2) (−24.2, 21.0) 0.9967  0.6 (−16.7,17.8) 0.9420 Treatment + n Baseline[2] Week 12 EP [3] Median % EstimatedStatin [1] Median (IQR) Median (IQR) Chg from BL (Q1, Q3) p-value median95% CI p-value hsCRP (mg/L) [4] Placebo 219 2.2 (4.0) 2.6 (4.7)  17.1(108.0) (−26.5, 81.5) <0.0001 — — — AMR101 2 g/d 227 1.9 (2.9) 2.5 (3.4)10.3 (88.6) (−24.3, 64.3) <0.0001 −6.8 (−20.0, 6.0) 0.2889 AMR101 4 g/d217 2.2 (2.7) 2.0 (3.0) −2.4 (62.8) (−29.4, 33.3) 0.5544 −22.0  (−34.1,−9.4) 0.0005 [1] Only patients with non-missing baseline and Week 12endpoint values were included. [2]Baseline was defined as the Visit 4(Week 0) measurement. If missing, the last valid measurement prior todosing with study rug was used. [3] The Week 12 endpoint was defined asthe Visit 7 (Week 12) measurement. If missing, the LOCF method was used.4. Post-hoc analysis of hsCRP based on median percent change frombaseline p-values are from Wilcoxon rank-sum test. When hsCRP = <0.2,0.1 was imputed for the analysis. CI = confidence interval; EP =endpoint; IQR = interquartile range; Q1 = first quartile; Q3 = thirdquartile

Table 22 shows changes in EPA concentration from baseline to week 12 inthe MITT group.

TABLE 22 Changes in EPA Concentration from Baseline to Week 12-MITT.Placebo AMR101 2 g Week 12 LS Mean Week 12 Baseline[2] Endpoint Change(SE) Baseline Endpoint Mean [3] Mean [4] From [3] Mean [4] MeanParameter n[1] (SD) (SD) Baseline n[1] (SD) (SD) Plasma EPA 81 28.1(28.01) 30.6 (27.90) 8.1 (6.59) 73 28.1 (13.71) 123.8 (67.82)concentration (μg/mL) RBC EPA 79 11.2 (6.64)  9.9 (5.70) 0.4 (2.38) 7110.9 (5.21)  43.7 (16.84) concentration (μg/mL) AMR101 2 g AMR101 4 g LSMean Week 12 LS Mean Change (SE) Baseline Endpoint Change (SE) [5] From[3] Mean [4] Mean [5] From Parameter Baseline n[2] (SD) (SD) BaselinePlasma EPA 100.5 (6.83) 71 28.1 (18.79) 182.6 (71.73) 159.5 (6.95)concentration (μg/mL) RBC EPA  34.6 (2.48) 69 11.6 (5.56)   72.7 (31.49) 62.8 (2.55) concentration (μg/mL) Outliers were identified within eachtreatment group as percent change values <Q1 − 1.5*IQR or >Q3 + 1.5*IQR.Patients with outliers were excluded from the analysis. When LLOQ was<10.0, 5 μg/mL was imputed for analysis. When LLOQ was <5.00, 2.5 μg/mLwas imputed for analysis. [1]Only patients with non-missing baseline andWeek 12 endpoint values were included. [2]Baseline was defined as theVisit 4 (Week 0) measurement. If missing, the last valid measurementprior to dosing with study drug was used. [3] The Week 12 endpoint wasdefined as the Visit 7 (Week 12) measurement. If missing, the LOCFmethod was used. [4] Least-squares means and SEs were from linearcontrasts of an ANCOVA model of change from baseline to Week 12endpoint, with treatment, gender, type of stain, and presence ofdiabetes as factors and baseline value as a covariate. ANCOVA = analysisof covariance; EPA = eicosapentaenoic acid; IQR = interquartile range;LLOQ = lower limit of quantitation; LOCF = last observation carriedforward; LS = least squares; Q1 = first quartile; Q3 = third quartile;RBC = red blood cell; SD = standard deviation; SE = standard error.

These data demonstrate that administration of 4 g per day of ethyleicosapentaenoate for 12 weeks resulted in atherogenic particleconcentarions that correlate with Apo B and, compared with placebo andrelative to baseline, reduce key atherogenic lipoprotein particleconcentrations and produce potentially beneficial reductions in FADI instatin-treated subjects at high atherosclerotic coronary heart diseaserisk.

Example 2 Effects of High Purity Ethyl-EPA on Lipoprotein ParticleConcentration and Size

The reductions in lipoprotein particle concentration and size for allrandomized subjects in the populations of Example 1 who had a baselinetriglyceride primary efficacy end point measurement, received at leastone dose of the ethyl EPA study drug or placebo, and had at least onepost-randomization efficacy measurement were studied.

As shown in Table 23, this subset of subjects had similar baselinetriglycerides, LDL-C, non-HDL-C, HDL-C and Apo-B levels to the ITTpopulation of Example 1. Subjects in this subset who received 4 g/dayof >96% ethyl-EPA of Example 1 (“IPE”) experienced similar significantreductions in triglycerides, LDL-C, non-HDL-C, HDL-C and Apo-B versusplacebo at 12 weeks that the larger ITT population of Example 1experienced in the same time period.

TABLE 23 Median Changes in Selected Lipid End Points After 12Weeks-Patients with Lipoprotein Data. Median IPE 4 g/day Placebo ChangeFrom (n = 216) (n = 211) Baseline Change Change IPE 4 g/day Lipid EndPoint End of From End of From vs Placebo, (mg/dL) Baseline TreatmentBaseline, % Baseline Treatment Baseline, % %, P TG 264.8 219.3 −17.5258.0 267.5 4.8 −21.1 (90.3) (91.3) (30.4) (80.5) (141.0) (43.6) <0.0001LDL-C* 82.0 83.0 2.1 84.0 88.0 7.7 −5.2 (24.0) (31.0) (27.0) (27.0)(31.0) (31.2) 0.0225 Non-HDL-C 128.0 122.0 −5.1 128.0 136.0 9.8 −13.5(32.5) (37.0) (21.4) (34.0) (42.0) (27.2) <0.0001 HDL-C 38.0 36.5 −2.239.0 40.0 5.2 −5.0 (12.0) (13.0) (18.5) (12.0) (14.0) (22.0) 0.0005Apo-B 92.5 90.0 −2.2 92.0 98.0 7.0 −8.8 (23.5) (25.5) (16.5) (25.0)(25.0) (23.0) <0.0001 Data are presented as median (interquartile range)for end point values. Median percent changes versus placebo areHodges-Lehmann medians. Apo-B, apolipoprotein B; HDL-C, high-densitylipoprotein cholesterol; IPE, icosapent ethyl; LDL-C, low-densitylipoprotein cholesterol; TG, triglycerides. *n = 210 for placebo.

As shown in Table 24, subjects receiving 4 g/day of the >96% ethyl-EPAcomposition for 12 weeks also had significantly reduced concentrationsof total VLDL particles, large VLDL particles, medium VLDL particles,total LDL particles, small LDL particles, total HDL particles and largeHDL particles compared to placebo. The treated subjects also hadsignificantly increased large LDL particle concentration compared toplacebo after 12 weeks. Treated subjects also had significantly reducedVLDL particle size, significantly reduced HDL particle size, andslightly increased LDL particle size compared to placebo after 12 weeks.

TABLE 24 Median Changes in Lipoprotein Particle Concentration and SizeAfter 12 Weeks- Patients with Lipoprotein Data. Median IPE 4 g/dayPlacebo Change From (n = 216) (n = 211) Baseline Change Change IPE 4g/day End of From End of From vs Placebo, Baseline Treatment Baseline, %Baseline Treatment Baseline, % %, P Lipoprotein Particle ConcentrationTotal VLDL, 116.7 110.0 −2.5 111.2 122.0 7.9 −12.2 nmol/L (66.6) (78.0)(41.8) (50.6) (60.0) (40.1) 0.0002 Large 12.9 7.7 −41.9 12.9 14.1 6.0−46.4 VLDL, (10.7) (7.6) (57.2) (9.7) (13.2) (101.1) <0.0001 nmol/LMedium 54.8 49.7 −6.9 53.3 58.8 9.2 −12.1 VLDL, (37.2) (41.8) (59.3)(29.9) (36.1) (56.3) 0.0068 nmol/L Small 43.9 46.8 8.3 41.4 45.3 8.5 2.8VLDL, (36.8) (39.9) (81.8) (32.8) (37.4) (70.0) 0.6321 nmol/L Total LDL,1131 1191 3.8 1152 1287 11.9 −7.7 nmol/L (369.5) (512.0) (31.8) (353.0)(456.0) (31.6) 0.0017 IDL, 51.5 63.0 23.7 55.0 55.0 0.0 10.0 nmol/L(81.5) (94.0) (173.7) (88.0) (102.0) (194.8) 0.3051 Large LDL, 113.5172.5 55.2 113.0 166.0 30.6 34.2 nmol/L (198.5) (226.0) (241.0) (215.0)(271.0) (200.4) 0.0076 Small LDL, 894.0 902.5 −1.1 902.0 978.0 11.0−13.5 nmol/L (266.5) (387.5) (36.1) (323.0) (387.0) (39.0) <0.0001 TotalHDL, 34.3 32.6 −4.0 34.8 35.5 4.7 −7.4 μmol/L (8.9) (8.2) (16.4) (10.1)(9.3) (16.2) <0.0001 Large HDL, 2.5 1.9 −21.6 2.8 2.9 9.1 −31.0 μmol/L(1.8) (2.0) (58.1) (2.0) (2.3) (50.4) <0.0001 Medium 6.7 6.9 4.2 7.8 8.38.6 −6.5 HDL, (6.0) (4.8) (69.4) (5.6) (7.3) (81.8) 0.2245 μmol/L SmallHDL, 24.2 23.1 −3.9 23.0 24.0 1.6 −2.8 μmol/L (6.4) (6.7) (21.9) (8.1)(7.4) (25.4) 0.1267 Lipoprotein Particle Size VLDL, 56.3 51.2 −8.1 56.555.9 −0.6 −7.7 nm (8.3) (8.4) (13.7) (10.0) (11.3) (14.3) <0.0001 LDL,*19.8 20.0 0.5 19.8 19.9 0.0 0.5 nm (0.5) (0.6) (2.5) (0.6) (0.5) (2.5)0.0031 HDL, 8.7 8.6 −1.1 8.7 8.7 0.0 −1.2 nm (0.3) (0.2) (3.5) (0.3)(0.4) (3.5) 0.0014 Data are presented as median (interquartile range)for end point values. Median percent changes versus placebo areHodges-Lehmann medians. Diameter as follows: large VLDL (>60 nm); mediumVLDL (42-60 nm); small VLDL (29-42 nm); IDL (23-29 nm); large LDL(20.5-23.0 nm); small LDL (18.0-20.5 nm); large HDL (9.4-14.0 nm);medium HDL (8.2-9.4 nm); and small HDL (7.3-8.2 nm). HDL, high-densitylipoprotein; IDL, intermediate-density lipoprotein; IPE, icosapentethyl; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.*n = 215 for IPE 4 g/day.

Atherogenic particle concentration (e.g., concentration of all VLDL andLDL particles) correlated well with ApoB concentrations at both baseline(FIG. 6A) and after 12 weeks (FIG. 6B). Similarly, total LDL particleconcentrations correlated strongly with ApoB concentrations at bothbaseline (FIG. 6C) and after 12 weeks (FIG. 6D).

What is claimed is:
 1. A method of lowering triglycerides in a subjecton statin therapy having baseline fasting triglycerides of about 200mg/dl to less than 500 mg/dl, the method comprising determining abaseline fasting triglyceride level associated with the subject; andthereafter administering to the subject about 2 grams or about 4 gramsper day of ethyl eicosapentaenoate.
 2. The method of claim 1 furthercomprising determining a baseline fasting LDL-C level associated withthe subject before the administering, wherein an LDL-C level associatedwith the subject after the administering is not increased compared tothe baseline fasting LDL-C level.
 3. The method of claim 1, wherein thesubject is administered about 2 grams per day of ethyleicosapentaenoate, and wherein the triglycerides are lowered by about10% compared to a second subject who has received statin therapy but notthe ethyl eicosapentaenoate.
 4. The method of claim 2, wherein thesubject is administered about 2 grams per day of ethyleicosapentaenoate, and wherein the triglycerides are lowered by about10% compared to a second subject who has received statin therapy but notthe ethyl eicosapentaenoate.
 5. The method of claim 1, wherein thesubject is administered about 4 grams per day of ethyleicosapentaenoate, and wherein the triglycerides are lowered by about21% compared to a second subject who has received statin therapy but notthe ethyl eicosapentaenoate.
 6. The method of claim 2, wherein thesubject is administered about 4 grams per day of ethyleicosapentaenoate, and wherein the triglycerides are lowered by about21% compared to a second subject who has received statin therapy but notthe ethyl eicosapentaenoate.
 7. The method of claim 1 further comprisingdetermining a baseline fasting Apo B level associated with the subject,wherein after the administering an Apo B level associated with thesubject is significantly lower than the baseline fasting Apo B levelcompared to a second subject who has received statin therapy but not theethyl eicosapentaenoate.
 8. The method of claim 1 further comprisingdetermining a baseline fasting VLDL-C level associated with the subject,wherein after the administering an VLDL-C level associated with thesubject is significantly lower than the baseline fasting VLDL-C levelcompared to a second subject who has received statin therapy but not theethyl eicosapentaenoate.
 9. The method of claim 1 further comprisingdetermining a baseline fasting LP-PLA₂ level associated with thesubject, wherein after the administering an LP-PLA₂ level associatedwith the subject is significantly lower than the baseline fastingLP-PLA₂ level compared to a second subject who has received statintherapy but not the ethyl eicosapentaenoate.
 10. The method of claim 1further comprising determining baseline fasting levels of LDL-C, Apo B,VLDL-C and Lp-PLA₂ associated with the subject, wherein after theadministering levels of LDL-C, Apo B, VLDL-C and Lp-PLA₂ associated withthe subject are significantly lower than the baseline fasting levelscompared to a second subject who has received statin therapy but not theethyl eicosapentaenoate.
 11. The method of claim 10, wherein the subjectreceives about 2 grams of ethyl eicosapentaenoate per day.
 12. Themethod of claim 10, wherein the subject receives about 4 grams of ethyleicosapentaenoate per day.
 13. The method of claim 2, wherein thesubject has a baseline fasting LDL-C level of about 82 mg/dl.
 14. Themethod of claim 7, wherein the subject has a baseline fasting Apo Blevel of about 217 mg/dl or about 227 mg/dl.
 15. The method of claim 8,wherein the subject has a baseline fasting VLDL-C level of about 225mg/dl or about 233 mg/dl.
 16. The method of claim 9, wherein the subjecthas a baseline fasting Lp-PLA₂ level of about 217 mg/dl or about 224mg/dl.
 17. The method of claim 10, wherein the subject has: a baselinefasting LDL-C level of about 82 mg/dl; a baseline fasting Apo B level ofabout 217 mg/dl or about 227 mg/dl; a baseline fasting VLDL-C level ofabout 225 mg/dl or about 233 mg/dl; and a baseline fasting Lp-PLA₂ levelof about 217 mg/dl or about 224 mg/dl.